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Copyright © 2009 Elsevier Inc. All rights reserved.
Molecular Cell, Volume 34, Issue 3, 259-269, 15 May 2009
Add/View Comments (0)A Role for Ubiquitin in Selective Autophagy
Vladimir Kirkin1, 3, , , David G. McEwan1, Ivana Novak2 and Ivan Dikic1, 2, ,
1 Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
2 Mediterranean Institute for Life Sciences, Mestrovicevo setaliste bb, 21000 Split, Croatia
Corresponding author
3 Present address: Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany
- Ubiquitination is the hallmark of protein degradation by the 26S proteasome. However, the proteasome is limited in its capacity to degrade oligomeric and aggregated proteins. Removal of harmful protein aggregates is mediated by autophagy, a mechanism by which the cell sequesters cytosolic cargo and delivers it for degradation by the lysosome. Identification of autophagy receptors, such as p62/SQSTM1 and NBR1, which simultaneously bind both ubiquitin and autophagy-specific ubiquitin-like modifiers, LC3/GABARAP, has provided a molecular link between ubiquitination and autophagy. This review explores the hypothesis that ubiquitin represents a selective degradation signal suitable for targeting various types of cargo, ranging from protein aggregates to membrane-bound organelles and microbes.
Main Text
Ubiquitin (Ub) is a small protein highly conserved from yeast to man. It was first described in the context of protein degradation, but later shown to participate in regulation of other cellular processes, such as endocytosis, signal transduction, and DNA repair (Kirkin and Dikic, 2007,Welchman et al., 2005) (Table 1). Conjugation of Ub is a complex reaction that requires E1, E2, and E3 enzymes and leads to the formation of an isopeptide bond between the C-terminal Gly of Ub and the ɛ-amino group of a Lys residue of the substrate protein (Hershko and Ciechanover, 1998). Due to the presence of internal Lys residues, Ub can repeatedly be attached to itself, forming chains with various topologies and functions (Ikeda and Dikic, 2008). Modification of a protein with Ub chains (polyubiquitination), in which Ub is linked via Lys48, targets the substrate to the proteasomal pathway, while attachment of a single Ub moiety (monoubiquitination) and/or oligomeric Lys63-linked Ub chains, i.e., during the process of endocytosis, marks substrate proteins for degradation in lysosomes (Welchman et al., 2005). Recent experimental data have provided evidence for the involvement of Ub in yet another fundamental lysosome-dependent degradation system, autophagy. This catabolic pathway, capable of targeting individual proteins, larger macromolecular complexes, and complete organelles, is of great importance for cellular homeostasis and survival, while its deregulation has been linked to pathological conditions, such as neurodegeneration and cancer (Ohsumi, 2001,Xie and Klionsky, 2007,Levine and Kroemer, 2008).
Table 1 |
UBL | Precursor Processing Enzymes | Activating Enzyme | Conjugating Enzyme(s) | Ligating Enzymes | Conjugation Substrate | Deconjugation Enzymes | Known Functions | |||
Yeast and human | Ub | DUBs | E1 enzyme | E2 enzymes | E3 ligases | various proteins | DUBs | acts as a signal for proteasomal and lysosomal degradation; provides a scaffold for signal transduction and DNA repair machineries | ||
Yeast | ATG8 | ATG4 | ATG7 | ATG3 | ATG5-ATG12 | PE | ATG4 | (1) mediates expansion of the phagophore via membrane tethering and hemifusion; (2) acts as a ligand for autophagic receptors: ATG19 (Cvt pathway in yeast) and p62 and NBR1 (in selective autophagy in higher organisms) | ||
Human | MAP1LC3A (LC3A) MAP1LC3B (LC3B) MAP1LC3C (LC3C)GABARAP GABARAPL-1 GABARAPL-2/GATE-16 GABARAPL-3 | ATG4A ATG4B ATG4C ATG4D | ATG7 | ATG3 | ATG5-ATG12 | PE | ATG4A ATG4B ATG4C ATG4D | |||
Yeast | ATG12 | - | ATG7 | ATG10 | - | ATG5 | - | as a conjugate with ATG5, has an E3-like activity toward ATG8 family proteins | ||
Human | ATG12 | - | ATG7 | ATG10 | - | ATG5 | - | |||
Yeast | ATG5 | - | - | - | - | - | - | (1) in complex with ATG16, acts as a scaffold for autophagosome formation; (2) as a conjugate with ATG12, has an E3-like activity toward ATG8 family proteins | ||
Human | ATG5 | - | - | - | - | - | - | |||
DUB, deubiquitinating enzymes; ATG, autophagy-related protein; PE, phosphatidylethanolamine; MAP1LC3, microtubule-associated proteins 1A/1B light chain 3; GABARAP, Gamma-aminobutyric acid receptor-associated protein; GABARAPL, Gamma-aminobutyric acid receptor-associated protein-like; GATE-16, Golgi-associated ATPase Enhancer of 16 kDa. |
The generic term "autophagy" comprises several processes by which the lysosome acquires cytosolic cargo, with three types of autophagy being discerned in the literature: (1) macroautophagy, characterized by the formation of a crescent-shaped structure (the phagophore) that expands to form the double-membrane autophagosome, capable of fusion with the lysosome; (2) microautophagy, in which lysosomes invaginate and directly sequester cytosolic components; and (3) chaperone-mediated autophagy (CMA), which involves translocation of unfolded proteins across the lysosomal membrane (Mizushima et al., 2008). As the main focus of this review is on the process of macroautophagy, we will refer to it throughout the text as simply autophagy.
While autophagosomes can sequester cytosolic material nonspecifically, for example, as a response to starvation, there is ample evidence for selective autophagic degradation of various cellular structures, including protein aggregates, mitochondria, and microbes (Xie and Klionsky, 2007). The mechanism of selective autophagy is not well understood; however, the involvement of Ub in this process is evident: analogous to the proteasome, where ubiquitinated cargo is delivered by Ub receptors (Elsasser and Finley, 2005,Husnjak et al., 2008), autophagic clearance of protein aggregates requires Ub-binding receptors p62 and NBR1 (Kirkin et al., 2009,Komatsu et al., 2007,Pankiv et al., 2007) (Figure 1 and Figure 2). It is envisaged that by simultaneous binding to both Ub and the autophagosome-associated Ub-like (UBL) proteins (i.e., LC3/GABARAP proteins), these molecules can mediate docking of ubiquitinated protein aggregates to the autophagosome, thereby ensuring their selective degradation. Here, we summarize available evidence for the role of Ub in autophagy and postulate that attachment of Ub moieties to various cellular cargos constitutes a universal degradation signal recognized by two major intracellular proteolytic systems: the proteasome and the lysosome.
Ubiquitin in Autophagic Degradation of Protein Substrates
Protein Misfolding and Aggregation
Protein misfolding, which results in the exposure of hydrophobic residues normally confined within the folded proteins, accompanies normal protein synthesis but can be dramatically enhanced by numerous stimuli, including endoplasmatic reticulum and oxidative stress, starvation, mutation, and heat shock (Goldberg, 2003). Misfolded polypeptides are recognized by molecular chaperones of the heat shock protein (HSP) family, which bind to and shield exposed hydrophobic surfaces from the cytosol while promoting protein refolding (Goldberg, 2003). In addition, HSPs interact with Ub E3 ligases, such as CHIP and Parkin (Imai et al., 2002), which promote substrate polyubiquitination and, thus, prime terminally misfolded polypeptides for degradation by the proteasome.
Protein aggregation occurs when protein misfolding is left unresolved by the chaperone-assisted refolding or proteasomal degradation. Polymerization of misfolded proteins is mediated by nonspecific hydrophobic interactions of partially unfolded polypeptide chains that can lead to the formation of microscopically visible structures known as inclusion bodies and aggresomes (Kopito, 2000) (Figure 2). For simplicity, inclusion bodies can be viewed as multiple intracellular foci into which misfolded protein oligomers are sequestered, whereas the aggresome is a structure formed via the retrograde transport of aggregated proteins on microtubules and is usually found at the microtubule organizing center (MTOC) (Kopito, 2000) (Figure 2). The biological role of protein inclusions is not entirely clear. They may play protective role by sequestering toxic misfolded protein species and providing the cell with an opportunity of delayed protein degradation (Bjorkoy et al., 2005,Kopito, 2000). Alternatively, they may inactivate the proteasome and mediate cytotoxicity (Bence et al., 2001). The dual role of inclusions highlights the vital importance of alternative degradation pathways that would be amenable to degradation of bulky substrates. Thus, inhibition of the proteasome potently induces autophagy, which serves as a compensatory mechanism for degradation of accumulating polyubiquitinated misfolded proteins.
The Autophagosome: The Door to Purgatory
The autophagosome can engulf bulky substrates, including membrane-bound organelles. Genetic analyses of yeast mutants with autophagic defects have identified more than 30 autophagy-related (ATG) proteins that govern generation and maturation of the autophagosome as well as its degradation in the vacuole (Suzuki and Ohsumi, 2007). The most important functional groups of ATG proteins, as illustrated by an extensive homology with mammalian genes, include: (1) ATG1 kinase complex (ATG1, ATG13 and ATG17); (2) PI3K complex (Vps34 and Atg6); and (3) two UBL systems (ATG12-ATG5 and ATG8 [Table 1]) (Suzuki and Ohsumi, 2007).
The autophagy-specific UBL proteins are of particular interest due to their similarity with Ub (Kirkin and Dikic, 2007) (Table 1). Thus, although ATG12 and ATG8 family proteins (known as LC3 and GABARAP proteins in mammalian cells) do not share any primary sequence homology with Ub, they structurally resemble Ub (Paz et al., 2000,Sugawara et al., 2004,Suzuki et al., 2005). They are also conjugated to their substrates, ATG5 and phosphatidylethanolamine (PE), respectively, via a C-terminal Gly residue (Ohsumi, 2001). Both ATG12 and ATG8 conjugation systems are required for autophagosome maturation. However, upon completion of this process, the ATG12-ATG5 complex dissociates from the autophagosomal membrane, while intravesicular ATG8 remains attached to the membrane through the fusion of the autophagosome with the lysosome (Ohsumi, 2001). This latter property has allowed the use of ATG8 and LC3 as autophagosomal markers (Klionsky et al., 2008). In the conjugated form, ATG8 can mediate tethering and hemifusion of lipid membranes (Nakatogawa et al., 2007). Therefore, ATG8 might constitute the driving force for the autophagosome expansion by tethering delivered lipid membrane components and facilitating their incorporation into the expanding phagophore.
Intimate involvement of UBLs in the autophagosome formation points at an interesting aspect of autophagosomal biology. The Ub fold is a widespread structural element in proteins involved in cell signaling, and the list of Ub-like proteins, existing both as small protein modifiers (classical UBLs) and as an integral part (domain) of larger proteins (Ub-like domain proteins, UDPs), has grown rapidly (Jentsch and Pyrowolakis, 2000,Kirkin and Dikic, 2007). Conjugated Ub moieties are recognized by Ub-binding domain (UBD)-containing proteins (Hicke et al., 2005), and similarly, we expect that autophagy-specific UBLs, via noncovalent interactions, may recruit components of signaling complexes to the nascent autophagosomes and/or provide a means of selectivity for certain types of autophagic cargo. Support for this hypothesis came from the identification of proteins that bind ATG8/LC3/GABARAP and facilitate selective degradation of misfolded and ubiquitinated proteins, p62 and NBR1 (Bjorkoy et al., 2005,Kirkin et al., 2009,Komatsu et al., 2007,Pankiv et al., 2007) (Figure 2).
Ubiquitin-Binding Proteins in Selective Autophagy
p62/SQSTM1—The Prototype Autophagic Receptor
p62/SQSTM1 is a multifunctional adaptor protein that has been implicated in cell signaling and differentiation (Moscat et al., 2007). It was originally characterized as an interaction partner of atypical protein kinase C (aPKC) (Puls et al., 1997,Sanchez et al., 1998), and this interaction was shown to be mediated by the conserved module found at the very N-terminus of p62, known as Phox and Bem1p (PB1) domain, which also mediates oligomerization of p62. p62 also possesses a zinc-finger domain and a C-terminal Ub-binding UBA domain (Figure 1). The UBA domain of p62 can bind both K48-linked and K63-linked Ub chains but with a higher affinity for K63 chains (Long et al., 2008,Tan et al., 2007,Wooten et al., 2008). The ability of p62 to interact with Ub has placed it into the focus of intense research. Thus, mutations in the UBA domain of p62 have been linked to the etiology of Paget's disease characterized by abnormal osteoclastogenic activity (Cavey et al., 2005). It is generally believed that the Ub-binding activity of p62 is essential for RANKL-NF-κB signaling that regulates osteoclastogenesis. However, the exact mechanism for the involvement of the p62-Ub interaction in the disease progression remains unclear. Further complicating the situation, p62 has been shown to affect NF-κB activation in an Ub/UBA-binding-independent manner (Moscat et al., 2007).
Several lines of evidence point at another important biological role of p62. Ub-positive inclusion bodies have been found positive for p62 (Nagaoka et al., 2004,Zatloukal et al., 2002). This prompted the Johansen group to hypothesize the involvement of p62 in autophagic clearance of aggregation-prone proteins with the idea that p62 might represent the missing link between the protein aggregation and autophagy. They were able to show that p62 was itself degraded by autophagy and formed a shell-like structure around experimentally-induced Ub-positive protein aggregates, which were also positive for LC3. This process was proposed to be dependent on the PB1 and UBA domains of p62 and, hence, on its ability to interact with itself and Ub (Bjorkoy et al., 2005). Subsequent experiments showed the physical interaction between p62 and LC3 (Komatsu et al., 2007,Pankiv et al., 2007) and LC3-Interacting Region (LIR) in human p62 was defined as a short linear peptide of 22 amino acids characterized by an acidic cluster (Asp-335, Asp-336, and Asp-337) and a conserved aromatic residue (Trp-340) (Pankiv et al., 2007).
Structural studies on the complex formed by the LC3 and the LIR of p62 showed that the WTHL tetrapeptide of the p62-LIR adopts a β-conformation and forms an intermolecular parallel β sheet with the β2-strand of LC3 (Ichimura et al., 2008,Noda et al., 2008). Importantly, the side chain of the conserved Trp in the WTHL motif binds deeply in the hydrophobic pocket formed at the interface between the N-terminal domain (α2) and the UBL domain of LC3. In contrast, the conserved Leu is engaged in the interaction with a hydrophobic pocket on the UBL domain itself (Ichimura et al., 2008,Noda et al., 2008). A similar motif (WEEL) was shown to be responsible for the interaction between ATG19 (Figure 1) and ATG8 in the Cvt pathway in yeast (Figure 3) (Noda et al., 2008), suggesting that the WxxL motif may define the LIR consensus sequence in otherwise unrelated ATG8/LC3-interacting proteins. This binding mode is reminiscent of the interaction between the SUMO-Interacting Motif (SIM) and SUMO involved in the regulation of transcription and nuclear protein import (Hecker et al., 2006).
LIR-deficient forms of p62 produce Ub-positive and LC3-negative aggregates in the cytoplasm of cells lacking endogenous p62. These protein aggregates also depend on the functional PB1 domain of p62, which underscores the relevance of the p62 oligomerization potential (Ichimura et al., 2008,Pankiv et al., 2007).
p62 is an LC3 interaction partner in vivo (Komatsu et al., 2007,Pankiv et al., 2007) and is constantly degraded by autophagy (Bjorkoy et al., 2005), establishing p62 as a useful marker for autophagic vesicle turnover (Klionsky et al., 2008). In support of this notion, mice with tissue-specific autophagy deficiency (Atg7 knockout mice) demonstrate accumulation of p62 in Ub-positive protein inclusions in neurons and hepatocytes (Komatsu et al., 2007). Curiously, the autophagy inhibition-associated toxicity observed in the liver cells differs from that seen in the brain with respect to p62 dependence: whereas removal of p62 alleviated liver impairment in Atg7−/−/p62−/− mice, these mice still suffered from neuronal death (Komatsu et al., 2007). As in both cell types removal of p62 led to dramatic reduction in microscopically visible protein aggregates, there are likely to be cell-type-specific functions that contribute to p62-associated toxicity in autophagy-deficient tissues. Similar to autophagy-deficient mice, fruit flies deficient in autophagy develop inclusions in neurons, which disappear when Drosophila's p62 homolog Ref(2)P is deleted (Nezis et al., 2008), highlighting the evolutionarily conserved role of p62 in protein inclusion formation.
The aggregate-promoting properties of p62 may explain why autophagy-proficient p62 knockout mice do not show strong accumulation of Ub-positive protein inclusions, as might be anticipated from the proposed role of p62 in mediating autophagic degradation of ubiquitinated proteins (Komatsu et al., 2007). Yet, an age-dependent buildup of Ub in neurons of p62−/− and associated neurodegeneration were reported (Wooten et al., 2008). One explanation for the delayed onset of the apparent neuron-specific autophagy defects in p62 knockout mice (in comparison to those seen in the Atg7- and Atg5-deficient mice [Hara et al., 2006,Komatsu et al., 2006]) may be the existence of functional homologs of p62 in higher organisms.
NBR1—The New Autophagy Receptor
NBR1 (Neighbor of BRCA1 gene 1) was originally cloned as a candidate gene for the ovarian cancer antigen CA125 (Campbell et al., 1994). Given the remarkable similarity in the domain organization (Figure 1) and direct interaction with p62, NBR1 has subsequently been studied in cell signaling and differentiation: in muscle cells, NBR1 is a signaling mediator downstream of the giant kinase titin (Lange et al., 2005). More recently, NBR1 was shown to be involved in autophagic degradation of ubiquitinated targets (Kirkin et al., 2009).
NBR1 was identified as a direct binding partner of the autophagosome-specific ATG8/LC3/GABARAP modifiers both in vitro and in vivo. Mutational analysis and peptide mapping studies indicated the presence of a LIR at the C terminus of NBR1, which comprises a modified WxxL motif (i.e., YIII, aa 732–735 in human NBR1) (Figure 1). The presence of the LIR ensures that, even in the absence of p62, NBR1 interacts with the autophagosome-associated UBLs and is degraded by autophagy. Inhibition of autophagy or deletion of the LIR domain leads to accumulation of NBR1 in vivo (Kirkin et al., 2009).
NBR1 binds Ub via its UBA domain with a bias toward the K63-linked polyUb chains (Kirkin et al., 2009). Importantly, recruitment of Ub-positive cargo into lysosomes is dependent on both p62 and NBR1. Like p62, NBR1 plays a role in cross-linking of ubiquitinated misfolded proteins and is necessary for puromycin-induced inclusion body formation and protein aggregation following a block in autophagy. NBR1 performs this function via self-association mediated by the coiled-coiled domain (Figure 1) and also via interaction with oligomeric p62 and ubiquitinated substrates (Figure 2). Interestingly, NBR1 is a component of the Mallory bodies, protein inclusions found in the liver of patients with alcoholic and nonalcoholic steatohepatitis (Kirkin et al., 2009).
HDAC6—A Ubiquitin- and Dynein-Binding Adaptor
Sequestration of misfolded, ubiquitinated proteins into aggregates may provide a protection mechanism, leading to reduced cytotoxicity and enhanced autophagic clearance of reactive protein species. However, when the rate of formation exceeds that of clearance, aggregates are delivered to MTOC-associated aggresomes. Therefore, aggresomes are thought to constitute a long-term repository of misfolded proteins en route for autophagic degradation (Figure 2). Since aggresomes frequently consist of ubiquitinated proteins, Ub-binding proteins may mediate their formation. The noncanonical histone deacetylase HDAC6 (Figure 1) has been implicated in this process (Matthias et al., 2008).
Experimentally induced Ub-positive aggresomes contained HDAC6, and siRNA-mediated depletion of HDAC6 compromised the aggresome formation, which could be rescued only by a Ub binding-competent form of HDAC6 (Kawaguchi et al., 2003). Curiously, this situation is reminiscent of p62 and NBR1, which are both recruited to Ub-positive aggregates and necessary for their formation. HDAC6 binds Ub via the C-terminal BUZ domain (Figure 1) that shows preference for K63-linked Ub chains (Olzmann et al., 2007). However, unlike p62 and NBR1, HDAC6 possesses no LIR. It interacts directly with dynein motors, which are necessary for transportation of aggregated misfolded proteins to the MTOC (Kawaguchi et al., 2003). The process of the active transport along the microtubules is essential for the aggresome formation, as microtubule-depolymerizing drugs efficiently inhibit this process (Rodriguez-Gonzalez et al., 2008). Importantly, lysosomes are enriched at the MTOC, and mature autophagosomes, like unwrapped protein aggregates, are transported along the microtubules for their fusion with lysosomes (Fass et al., 2006). Thus, aggresomes might allow concentration of all the necessary components for efficient autophagic clearance of aggregated proteins.
HDAC6 was required for autophagic degradation of mutant proteins during proteasomal inhibition. Here, HDAC6 influenced both the recruitment of autophagy-specific proteins to the aggregates and the lysosomal dynamics (Iwata et al., 2005,Pandey et al., 2007). In addition, aggresome formation and its autophagic degradation was dependent on deacetylase activity of HDAC6, which influenced microtubule dynamics (Iwata et al., 2005,Kawaguchi et al., 2003,Matthias et al., 2008,Pandey et al., 2007). Curiously, a very recent report defines acetylation of mutant huntingtin as a prerequisite for its autophagic degradation (Jeong et al., 2009). More work is necessary to understand the role of acetylation in protein degradation.
Other Proteins Involved in Selective Autophagy of Ubiquitinated Proteins
Besides proteins that directly bind Ub, there are several players that lack discernable UBDs but have been found associated with both ubiquitinated proteins and autophagosomal markers. One such protein is Alfy (Figure 1), a 400 kDa protein that contains the PtdIns(3)P-binding FYVE domain. Via this domain, Alfy may interact with autophagosomal membranes, as PtdIns(3)P is important in endosomal and autophagosomal membrane traffic (Simonsen et al., 2004). It is presently unknown how Alfy is recruited to ubiquitinated cargo.
Further, a senescence-activated Hsc/Hsp70 cochaperone BAG3 (Figure 1) has been proposed to mediate autophagic degradation of ubiquitinated proteins in aging cells (Gamerdinger et al., 2009). BAG3 colocalizes with p62-positive protein aggregates and autophagic markers and can stimulate autophagic flux. Intriguingly, although interacting with p62, BAG3 itself is not degraded by autophagy. In younger cells, BAG3 is poorly expressed, whereas the related cochaperone BAG1 plays a much more prominent role. In contrast to BAG3, BAG1 mediates proteasomal degradation of ubiquitinated proteins. It is thought that changes in the ratio between BAG1/BAG3 proteins might provide a mechanism for autophagic pathway activation during execution of the senescence program (Gamerdinger et al., 2009).
Ubiquitination at the Crossroads of the Autophagy and Proteasomal Pathways
Ubiquitinated cytosolic proteins undergo degradation via one of the two major routes: the proteasome or the lysosome. What determines whether a given Ub-labeled protein substrate will enter one or the other pathway? Classically, conjugation with K48-linked polyUb chains allows recognition of the proteolytic substrate by UBD-containing proteasomal receptors, whereas the K63-linked chains have been associated with nonproteolytic functions of Ub (Welchman et al., 2005). However, more recently, K63-linkage has been implicated in proteolytic degradation of misfolded and aggregated proteins (Olzmann et al., 2007,Tan et al., 2008,Wooten et al., 2008). Given the reported preference of the known Ub-binding autophagy receptors for K63-linked Ub chains, K63 Ub chain-marked cargo may be preferentially targeted to the autophagy/lysosomal degradation pathway in vivo.
On the other hand, p62 has been shown to compete for ubiquitinated cargo with the classical proteasomal receptors. Inhibition of autophagy and accumulation of p62 slowed down degradation of regular (short-lived) proteasomal substrates, most likely due to the excessive interaction between stabilized oligomeric p62 and K48 Ub-conjugated substrates (Korolchuk et al., 2009). Intriguingly, p62 has also been suggested to directly interact with the proteasome (Seibenhener et al., 2004), which raises the question whether autophagy receptors may have a more direct role in proteasomal degradation of ubiquitinated proteins.
Although polyUb chains are most frequently associated with proteolytic degradation, monoubiquitination may be sufficient as a signal for selective autophagy. While monoUb-driven autophagy depends on p62 (Kim et al., 2008), low affinity of the p62 UBA domain toward monoUb (Kirkin et al., 2009,Long et al., 2008) suggests that other factors, such as substrate/receptor oligomerization, will play a role in selective degradation of monoubiquitinated cargo by autophagy.
Deubiquitination is an important step in the proteasomal degradation of polyubiquitinated proteins. Ub moieties are necessarily removed from the substrate protein prior to its insertion into the narrow opening of the proteasome. In contrast, the autophagosome is able to take up bulky substrates, ranging from protein aggregates to membrane-bound organelles, and deliver them for degradation in the lysosome. Yet, deubiquitination may be involved in autophagy to reduce bulkiness of a complex substrate and/or to allow Ub recycling. For instance, p62-dependent autophagic degradation of ubiquitinated midbody ring structure, which physically separates two daughter cells during cytokinesis, involves gradual loss of Ub signal (Pohl and Jentsch, 2009). The latter phenomenon may, however, be explained by slow degradation kinetic of this large structure, which might have allowed observation of its integral components long after Ub-specific signal had been degraded.
Mitophagy, Pexophagy, Ribophagy, Xenophagy: Many Names, One Mechanism?
The autophagosomal membrane is envisaged to enwrap structures of varying size and geometry. This property of the autophagosome ensures that highly complex cytosolic cargo, including ribosomes and mitochondria, is efficiently degraded by autophagy, for instance, during a starvation response (Klionsky et al., 2008). While forming autophagosomes can engulf substrate rather stochastically, mounting evidence suggests that, similar to ubiquitinated proteins, ribosomes, mitochondria, peroxisomes, and intracellular bacteria may all be selectively targeted for autophagic degradation.
Ubiquitin in Selective Degradation of Mitochondria
Mitochondria provide an important example of selective autophagy of organelles. Damage and loss of mitochondrial potential are proposed to lead to targeted autophagic degradation of this organelle, aptly named mitophagy (Elmore et al., 2001). Spectacular enveloping of fluorescently labeled mitochondria with GFP-LC3-positive autophagosomes during the starvation-induced mitophagy in hepatocytes derived from GFP-LC3 transgenic mice provide compelling evidence for the existence of this process (Kim et al., 2007). Opening of the mitochondrial permeability transition (MPT) pore and subsequent rupture of the outer mitochondrial membrane is likely to cause release of as yet unknown autophagy-promoting factors. Several proteins found in yeast to be associated with mitochondrial membranes, such as Uth1p (Kissova et al., 2004) and Aup1 (Tal et al., 2007), are reported to be indispensable for the process of mitophagy. In mammals, mitochondria-localized BH3 domain-only protein BNIP3L/NIX (Figure 1) was shown to be critically involved in the entrapment of mitochondria by autophagosomes during the programmed elimination of mitochondria in maturing reticulocytes (Sandoval et al., 2008,Schweers et al., 2007).
In the absence of published evidence for a clearly defined signal for autophagic targeting of superfluous or damaged mitochondria, we consider the possibility that induced conjugation of monoUb/Ub chains to an exposed mitochondrial protein may provide the missing link between the mitochondrion and the autophagosome (Figure 4). E3 ligases, residing in or at the mitochondrial membranes (Chu et al., 2009,Li et al., 2008), may regulate this process. Alternatively, induced recruitment of cytosolic E3 ligases can also be envisaged. Recently, Parkin has been shown to be recruited to depolarized mitochondria and mediate their autophagic degradation (Narendra et al., 2008). It remains to be determined what the ubiquitinated substrates on the mitochondrial membranes are and whether the known autophagic receptors, p62 and NBR1, could provide the mechanistic link between mitochondrial depolarization, ubiquitination, and mitophagy.
Interestingly, early studies on mitochondrial degradation in reticulocytes suggested that the process was Ub dependent (Rapoport et al., 1985). Supportive evidence also comes from the reports that describe ubiquitination of sperm mitochondria during their selective destruction after fertilization in mammals (Sutovsky et al., 1999,Sutovsky et al., 2000). More work is necessary to unequivocally demonstrate the role of mitochondrial ubiquitination in mitophagy.
Ubiquitination of Peroxisomes and Selective Autophagy
Peroxisomes constitute another type of organelle that undergoes regulated autophagic degradation, commonly referred to as pexophagy. In methylotrophic yeast, both micropexophagy (direct engulfment of the organelle by the vacuole) and macropexophagy (autophagosome-mediated delivery of peroxosomes to the vacuole) can be experimentally induced during yeast adaptation to an alternative carbon and energy source, such as glucose or ethanol (Dunn et al., 2005). Several peroxisomal proteins have been shown to be essential for both forms of pexophagy in yeast, with ATG30 being proposed to bind both the proteins found on the peroxisome (Pex3 and Pex14) and those involved in autophagosome formation (ATG11 and ATG17) (Farre et al., 2008). Yet, the signal present on peroxisomes that initiates selective degradation of these organelles has not been defined.
It seems plausible that Ub is involved in pexophagy (Figure 4). Several peroxisomal targeting signal (PTS) receptors (Pex5, Pex18, and Pex20) are subject to both mono- and polyubiquitination by cytosolic and peroxisomal Ub-conjugating machineries (Platta and Erdmann, 2007). While polyubiquitination of Pex5 is thought to promote its degradation, receptor monoubiquitination reportedly mediates extraction of the PTS receptor from the peroxisomal membrane to ensure its recycling and availability for the next round of importing of peroxisomal resident proteins (Platta et al., 2007). It is tempting to speculate that pexophagy might be triggered or promoted by prolonged retention of ubiquitinated proteins in the peroxisomal membrane. Strikingly, experimental fusion of a single Ub moiety to an integral membrane peroxisomal protein, PMP34, is sufficient to induce autophagic degradation of peroxisomes in mammalian cells. This form of pexophagy is partially dependent on the functional p62, suggesting involvement of p62 in selective autophagy of peroxisomes (Kim et al., 2008).
Ubiquitination in Selective Elimination of Ribosomes
Very recently, a novel mechanism for selective removal of ribosomes, i.e., ribophagy, in yeast was proposed. By labeling ribosomal proteins with GFP, Kraft et al. demonstrated that ribosomes are specifically targeted to the vacuole upon starvation, the process dependent on functional autophagic machinery. Importantly, genetic screens identified a Ub-specific protease, Ubp3, and an associated factor, Bre5, as proteins essential for ribophagy, but not for more general substrate degradation during starvation-induced autophagy. Moreover, ubiquitination of several ribosome-associated proteins was strongly increased in yeast deficient for Ubp3 (Kraft et al., 2008). While the authors propose that deubiquitination may assist in packaging of ribosomal components in the autophagosome, it is equally possible that, prior to the deubiquitinating step, Ub chains may serve as a signal for targeted elimination of ribosomes. More work is necessary to understand what triggers ubiquitination of ribosomal proteins during starvation and whether ubiquitination per se is a prerequisite for selective degradation of ribosomes by autophagy (Figure 4).
Ubiquitination as Antibacterial Mechanism
Autophagy emerges as an important mechanism for clearing intracelullar pathogens and, in this context, is referred to as xenophagy. Several medically relevant bacteria, including Mycobacterium tubercuolosis, Salmonella enterica, and Listeria monocytogenes are degraded by autophagy in vitro. Importantly, coevolution of the pathogens with the host's innate immune response system has allowed some intracellular bacteria to develop mechanisms that ensure evasion or even hijacking of the autophagic machinery for their own benefit (Levine and Deretic, 2007). Similar to the selective degradation of organelles, the specific signal that mediates recognition of intracellular pathogens by the autophagosome has not been defined thus far. However, a potential role for Ub signaling in xenophagy is emerging. For example, Ub was recognized as a vital factor in plant resistance to bacterial pathogens (Nishimura and Somerville, 2002), and association with Ub chains was demonstrated for both gram-negative and gram-positive intracellular bacteria (Perrin et al., 2004). Intriguingly, only free cytosolic bacteria, but not those found within acidic vacuoles, were positive for Ub. As proteasomes were recruited to ubiquitinated Salmonella typhimurium, authors proposed that bacteria-associated Ub might signal local degradation of bacterial proteins, thereby restricting their growth and stimulating presentation of bacterial antigens via MHC class I molecules (Perrin et al., 2004). We hypothesize that Ub associated with intracellular pathogens, similar to ubiquitination of protein aggregates, promotes targeted autophagosome formation and pathogen destruction. It remains to be seen whether autophagy receptors, such as p62 and NBR1, can link bacterial ubiquitination with the autophagic machinery and, thereby, mediate xenophagy (Figure 4).
Conclusions and Perspectives
Autophagy has generally been considered as a "nonselective" process. Yet, a growing body of evidence suggests that autophagy can be selective in targeting protein complexes, organelles, and microbes. Characterization of the molecular mechanisms, which govern the specificity, is still in its infancy but has been made possible by the identification of ATG proteins that regulate nucleation and maturation of the autophagosome in yeast. The central question of selective autophagy is how a particular substrate can engage the autophagosomal machinery to mediate phagophore assembly at a specific cellular location. The Cvt pathway in yeast may provide an answer to this question (Figure 3): in this prototypic pathway, preApe1 aggregates are recognized by a receptor protein (ATG19) that recruits and activates components of the autophagic machinery (Suzuki and Ohsumi, 2007). It is tempting to speculate that accumulation of ubiquitinated cargo might mimic this process via receptor-like proteins leading to targeted phagophore nucleation (Figure 3). Discovery of p62 and NBR1 as autophagy receptors, which interact with both Ub and UBLs of the ATG8 protein family, is an important step in exploring this hypothesis. Presence of p62/NBR1 homologs with identical functions in lower organisms demonstrates conservation of the mechanisms of Ub-mediated autophagy during the course of evolution (Nezis et al., 2008). It will now be essential to show whether ubiquitination is also involved in selective autophagy in yeast and to identify functional p62/NBR1 orthologs to allow dissection of the process in this established model system for selective autophagy.
Targeted degradation of misfolded proteins, damaged organelles, and microbes by autophagy is an important avenue of research that holds promise of new therapeutic approaches in treatment of cancer, neurodegenerative diseases, and infectious diseases. We propose that induced ubiquitination on the cargo surface provides a signal that leads to autophagosome formation. This phenomenon may provide an exciting opportunity to modulate levels of selective autophagy in different pathological conditions as illustrated by the recent progress in therapeutic targeting of the Ub system in cancer. However, while ubiquitination of peroxisomes, mitochondria, and pathogens has been formally demonstrated, much work is required to prove Ub as a universal degradation signal valid also for these targets.
By analogy to other Ub-regulated processes, ubiquitination of autophagic substrates has to be tightly regulated. Some of the key questions in this respect are what is the upstream signaling that results in the recruitment of dedicated E3 ligases to the autophagy substrate? Which E3 ligases are specific for selective autophagy of the respective substrates? What is the nature of the Ub signal as primary proautophagic event—is it monoUb or Ub chains of a specific topology? Furthermore, it is unclear what the role of TOR signaling in Ub-mediated autophagy is and how Ub-binding autophagic receptors (via interaction with ATG8 family proteins) are able to translate the Ub signal into the autophagosome formation process. Proteomic analysis of molecular complexes in vivo will likely identify the mechanistic links between ubiquitination and autophagy, which will require extensive genetic and functional characterization.
We would like to thank Terje Johansen and Trond Lamark for critically reading the manuscript. We apologize to those investigators whose contributions are not described here because of space limitations. I.N. is supported by a long term EMBO postdoctoral fellowship. I.D. acknowledges support from the Deutsche Forschungsgemeinschaft and the Cluster of Excellence "Macromolecular Complexes" of the Goethe University Frankfurt (EXC115).
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DC tops list of nation's worst traffic by Elizabeth Sheld Feb 6, 2013 8:21 AM PT DC gridlock is not just a metaphor, according to a study by Texas A & M Transportation Institute. Rankings of the nation's most congested cities vary slightly from year to year, and many of this year's top 10 are repeat performers. Washington, D.C. tops the list, followed by Los Angeles, San Francisco-Oakland, New York-Newark and Boston. Continue reading Share This: Read more
Stop-and-frisk works so what's the objection? by David Webb Feb 4, 2013 11:57 PM PT Stop-and-frisk works in New York City so why does the left fight it so hard and why not institute it in crime-ridden areas across the country. Stop-and-frisk defined.Continue reading Share This: Read more
One Finger Salute to Judge Lands 18 Year Old Jail Time by Liberty Chick Feb 4, 2013 6:58 PM PT If you're ever arrested for illegal possession of Xanax, you might want to be on your best behavior for the judge deciding your bail. More specifically, it's not a good idea to hurl expletives at the judge and then flip him the finger. It's apparently a lesson that was missed on 18 year old Penelope Soto during a Miami-Dade Circuit Court hearing.Continue reading Share This: Read more
This Guy, Myself, Really Impressed Me with My Thoughts by Ace Of Spades Feb 4, 2013 2:46 PM PT In response to myself, in Psychoanalyzing the Left: I thought this article I wrote was just great. I began reading what I wrote as a skeptic but by the end I had me utterly convinced. I fully exceeded my own high expectations of myself. Just when I thought I couldn't get any better, I did. I just completely took myself by surprise -- no easy accomplishment, either, as I'm a keen student of my own work with a nigh-encyclopedic knowledge about myself. Continue reading Share This: Read more
Obama's gratuitous attack on the Boy Scouts by Joel B. Pollak Feb 4, 2013 8:20 AM PT You don't have to support the Boy Scouts' ban on gay scoutmasters to be alarmed that President Barack Obama thinks that topic is an appropriate area for intervention or comment. The Obama administration does not believe there are any limits to its reach--not football, not religious institutions, not the Cambridge, MA police department--nothing. Continue reading Share This: Read more
This Day in History Where Blacks Contributed to the Founding American Idea by Jerome Hudson Feb 3, 2013 10:20 PM PT It's amazing what you learn when you look back. Sixty years ago today, Autherine J. Lucy became the first black student to be admitted to the University of Alabama. However, Lucy was suspended just three days later because the threats on her life and the mobs who were protesting her, made it too dangerous for Lucy to continue to come to campus. Continue reading Share This: Read more
Charlie Crist's Political Jock-Strapping by Javier Manjarres Feb 3, 2013 12:17 PM PT In response to President Obama throws a football!:Ben's post reminds me of another one of Obama's pals, former Republican Governor Charlie Crist, who also liked to think that he was some kind of a jock. Many of you may remember the time I played football with Charlie during the 2010 Senatorial campaign. Charlie's pass to me was staged in hopes that he would be able to show voters that he and I were buddies, and that perhaps I was not as supportive of Rubio. They knew better.Continue reading Share This: Read more
President Obama throws a football! by Ben Shapiro Feb 3, 2013 10:14 AM PT In his ongoing quest to convince the American people that he is a regular guy -- just like us! -- President Obama has now released a photo of himself getting ready to throw a football. The caption: "Game day." Obama's Super Bowl enthusiasm comes days after he suggested that his fictional son (not Trayvon, the other one) would not play football. If Obama throws this football like he throws a baseball, this pass will travel approximately 3.7 yards. Talk about a lame duck. Share This:
This Day in History Where Blacks Contributed to the Founding American Idea by Jerome Hudson Feb 2, 2013 6:25 PM PT Who loves Ice cream? Well, 116 years ago today, inventor and business man, Alfred L. Cralle was granted U.S. patent #576395 guaranteeing the rights to his invention of the ice cream scoop. Cralle was bothered by how difficult ice cream was to dispense and came up with an idea to solve the problem. Today, the ice cream scoop is still in use around the world. If that's not American ingenuity, I don't know what is. Continue reading Share This: Read more
NC school tells boy,9, to leave My Little Pony lunch bag at home, report says15 Mar 2014, 6:19 AM PDT

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Renee Hobbs is Professor and Founding Director of the Harrington School of Communication and Media at the University of Rhode Island, a new communication school that brings together the departments and programs in Journalism, Film/Media, Communication Studies, Public Relations, Writing & Rhetoric and a graduate program in Library and Information Studies, with 1300 undergrads, 350 grads and more than 80 fulltime faculty. Supported by a generous gift by Dick Harrington, former CEO of Thomson/Reuters, Renee Hobbs will help the faculty to create a new school of national distinction, charged with the mission of using the power of communication and digital media to make a difference in the world.
About Renee Hobbs. Professor Hobbs is one of the nation's leading authorities on media literacy education. Through community and global service and as a researcher, teacher, advocate and media professional, Hobbs has worked to advance the quality of digital and media literacy education in the United States and around the world. She founded the Media Education Lab, whose mission is to improve the quality of media literacy education through research and community service. In the early 1990s, she created the first national teacher education program in media literacy, the Harvard Institute on Media Education at the Harvard Graduate School of Education.
Research. Renee Hobbs maintains an active research agenda that examines the intersections of the fields of media studies and education. She has published dozens of articles in scholarly journals in three fields: communication, education and health. She is the founding co-editor of the Journal for Media Literacy Education, an open-access peer reviewed journal. Her current work with European colleague Dr. Silke Grafe of Ruhr-Universität Bochum in Germany examines teacher motivations for integrating digital tools and media literacy concepts into the curriculum. She has developed and validated measures of media literacy competencies for adolescents and is now working on approaches to assess the competencies of young children. Her book, Digital and Media Literacy: Connecting Culture and Classroom offers portraits of how secondary educators integrate critical thinking and communication skills across the curriculum. Her book, Copyright Clarity: How Fair Use Supports Digital Learning helps teachers understand copyright law as it applies to the use of digital media in education. Reading the Media: Media Literacy in High School English provides the first large-scale empirical evidence of the impact of media literacy education on reading comprehension skills. She also co-authored Elements of Language, the first secondary English language arts textbook to incorporate media literacy. Hobbs also offers program evaluation services for multimedia education with clients including PBS Student Reporting Labs and Project Look Sharp at Ithaca College.
Teaching. Hobbs offers graduate and undergraduate courses in mass media, children and adolescence, digital and media literacy education, youth media culture, and educational multimedia production. She supervises graduate students in the fields of media studies and education. Hobbs uses inquiry learning practices and emphasizes the role of students as content creators through digital multimedia. She is an experienced teacher educator and offers staff development programs to educators all across the United States and around the world.
Advocacy. Renee Hobbs works to increase visibility for digital and media literacy at the national level. In 2012, she serves as a Fellow for the American Library Association Office of Information Technology Policy. As a field-builder, she helped found the Partnership for Media Education, which evolved into the National Association for Media Literacy Education (NAMLE), the national membership organization for media literacy. She has sought exemptions to the Digital Millennium Copyright Act (DMCA) to advance the benefits of digital learning for all teachers and students. She is also active in helping educators understand their rights and responsibilities when using mass media, popular culture and digital media in education. Her white paper, Digital and Media Literacy: A Plan of Action offers a blueprint of pragmatic actions to bring these competencies to all Americans. It was released in Washington D.C. in November, 2010 and published by the Aspen Institute and the Knight Commission on the Information Needs of Communities in a Democracy.
Community and Global Service. With her colleagues at the Media Education Lab, Hobbs developed Powerful Voices for Kids, a university-school partnership that offers a comprehensive program for K-12 schools including a summer enrichment program for children, staff development program, hands-on mentoring and curriculum development, and parent and community outreach. She has worked in Italy, the Netherlands, Brazil, Argentina, France and China to help bring media literacy education to students and teachers worldwide. She partnered with the United Nations Alliance of Civilizations to explore how media literacy can promote mulicultural understanding, particularly of the peoples and cultures of the Middle East.
Media Production. Renee Hobbs is a multimedia producer and has developed numerous award-winning resources for K-12 students and educators that help develop digital and media literacy competencies. Assignment: Media Literacy was developed with support from the Maryland State Department of Education and the Discovery Channel. With support from the U.S. Office on Women's Health, she created My Pop Studio, an award-winning online edutainment game that introduces tween girls to media literacy concepts and takes girls "behind the scenes" of popular music, television, magazines, and online media. She also created an online education program for integrating social media into the teaching of the 2008 Presidential election, with support from PBS Teachers. Access, Analyze, Act: A Blueprint for 21st Century Civic Engagement is an interactive website for teachers designed to strengthen their ability to use social media tools developed by the PBS community. Her documentary video, Tuning in to Media, won the Parent's Choice Award in 1994.
Renee Hobbs received an Ed.D in Human Development from the Harvard Graduate School of Education, an M.A. in Communication from the University of Michigan, and a B.A. with a double major in English Literature and Film/Video Studies from the University of Michigan.
Click here to access her current CV and read more about her early work to develop the field of media literacy education. View a video interview with her aobut her leadership in media literacy.
Renee offers presentations, keynote addresses, workshops and seminars. Contact Renee directly at firstname.lastname@example.com or phone (401)874-2110 for more information.


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PITTSBURGH -- A Pennsylvania man wanted in a 2010 slaying in Clarksburg was arrested at his home Friday by U.S. Marshals.
Police in Clarksburg issued an arrest warrant Sept. 19 for Darnell "Nish" Carlton Bouie, 35, on a first-degree murder charge.
Police said Bouie and Ennis Charles Payne, 37, fatally shot Jayar "Trevor" Poindexter on Jan. 13, 2010, on Overlook Drive in Clarksburg.
Payne turned himself into police Sept. 18 and he was charged with first-degree murder.
U.S. Marshals negotiated Bouie's surrender with his attorney and he was supposed to turn himself in Sept. 21 in Pittsburgh, according to a news release issued by the U.S. Marshals service. However, Bouie didn't show up, according to the release. Marshals surrounded Bouie's home in Butler, Pa., Friday and he was arrested without incident.
Bouie was expected to go before a Pennsylvania magistrate Friday night. He was in custody awaiting an extradition hearing back to Clarksburg, according to the release.
Payne is being held without bail in North Central Regional Jail awaiting trial.


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Recipe by HappyMama
"Moist, delicious, and at least quasi-healthful. I was very pleased with how they turned out."
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1 tablespoon butter for greasing, or as needed (optional)
3/4 cup white sugar
1/4 cup vegetable oil
1/4 cup mayonnaise
2 eggs
3 bananas, mashed
1 1/4 cups all-purpose flour
1/2 cup quick cooking oats
1/4 cup ground flax
1/4 cup wheat germ
1 teaspoon baking soda
1 teaspoon baking powder
1 teaspoon salt
3/4 cup miniature semisweet chocolate chips
3/4 cup walnuts, chopped
These are really good! I added a teaspoon of vanilla (couldn't help myself!), the chocolate chips I used were just regular sized, and the oil I used was lemon olive oil. Otherwise, I followed the recipe. These baked for exactly 25 minutes, and I got 16 muffins. I'd imagine that rather than the mayonnaise that you could use yogurt or sour cream, and next time I'll try white whole wheat flour. These are ingredients I always have on hand, so whenever I have ripe bananas, I now have several healthy muffins to choose from. Thank you so much, Happy Mama.
1 Rating
* Percent Daily Values are based on a 2,000 calorie diet.
Chocolate Chip Banana Nut Muffins
Serving Size: 1/12 of a recipe Servings Per Recipe: 12 Amount Per Serving Calories: 349 Calories from Fat: 177
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Burn FX Kit
Item# 01111301
Create or complete a gruesome costume when you employ this Burn FX kit - the results can be simply monstrous. Next time, stay out of the acid rain and refrain from lighting a cigarette while gassing up the car!
- The Burn FX Kit consist of 2 burn scars, blood gel, flesh latex, injury stack, stipple sponge, makeup sponge and 2 stir sticks
In Stock & Ready to Ship
- Includes: 2 burn scars, blood gel, flesh latex, injury stack, stipple sponge, makeup sponge, 2 stir sticks
- Not included: shirt
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[1 of 2 customers found this review helpful]
By Alex the bailey from Winston salem, North Carolina on 9/11/2012
Authentic Looking
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Yes, I would recommend this to a friend
Comments about Burn FX Kit:
This was great i put just a little on my hand and i fooled all my friends they though i was lying when i said it was fake
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Silva bundles in Manchester City's fifth
FA Cup - 1 year ago
Watching: David Silva finishes from close range to extend the reigning champions' lead.
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42 U.S. Code § 16531 - Definitions
(Pub. L. 110–69, title V, § 5002,Aug. 9, 2007, 121 Stat. 600.)
References in Text
This subchapter, referred to in introductory provisions, was in the original "this title", meaning title V of Pub. L. 110–69, Aug. 9, 2007, 121 Stat. 600, known as the Protecting America's Competitive Edge Through Energy Act and also as the PACE–Energy Act, which is classified principally to this subchapter. For complete classification of this title to the Code, see Short Title of 2007 Amendment note set out under section
15801 of this title and Tables.
Short Title
For short title of title V of Pub. L. 110–69, which enacted this subchapter, as the "Protecting America's Competitive Edge Through Energy Act" or the "PACE–Energy Act", see section 5001 ofPub. L. 110–69, set out as a note under section
15801 of this title .
The table below lists the classification updates, since Jan. 3, 2012, for this section. Updates to a broader range of sections may be found at the update page for containing chapter, title, etc.
The most recent Classification Table update that we have noticed was Tuesday, August 13, 2013
An empty table indicates that we see no relevant changes listed in the classification tables. If you suspect that our system may be missing something, please double-check with the Office of the Law Revision Counsel.
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LAS CRUCES >> A former detective is facing more sex crime charges, less than two weeks after authorities charged him with the sexual assault of a teenage girl.
Michael Garcia, 37, has been charged with eight felony counts, according to the Magistrate Court's online data and an LCPD news release. The felony charges are a mix of criminal sexual contact and criminal sexual penetration, all against a minor.
Garcia, who lives on the 5800 block of Megan Street in Santa Teresa, was arrested Wednesday by his former LCPD colleagues and booked into the Doña Ana County Detention Center on a $50,000 bond, according to a news release.
Records show a criminal complaint has been filed by a Las Cruces Police Department investigator, but those documents have been sealed by Magistrate Judge Conrad Perea. Court manager Bernice Ramos described such an action as "rare," adding that Perea granted a motion to seal the file to protect the identity of the victim.
LCPD identified this victim only as a young girl, noting that she was "10 or 11 years old" when the alleged crimes began, and that they continued through her high school years. Online court records show the alleged crimes happened between 2004 and 2008. LCPD added that Garcia knew the girl outside his police employment.
Steve Almanza, Garcia's attorney, said Wednesday he is still investigating the new charges but does not believe his client is guilty.
Garcia resigned last week from LCPD. He had been an officer there for 15 years, most recently as a detective specializing in crimes against children.
LCPD had placed Garcia on standard administrative leave Aug. 23, after he was arrested and charged with sexually assaulting a different teenage girl inside his unmarked car in May 2011, according to a court document.
For that alleged incident, Garcia is facing separate but similar charges, criminal sexual penetration, a fourth-degree felony and second-degree criminal sexual contact. He had posted, for those charges, a $20,000 bond and left the Doña Ana County Detention Center the same day of his initial arrest.
In an interview with an LCPD detective after his Aug. 23 arrest, Garcia admitted to the sexual acts alleged by the girl, according to a criminal complaint. The detective that interviewed Garcia noted that Garcia seemed "remorseful."
Almanza said Wednesday that encounter was consensual.
The day after the arrest, LCPD issued a news release saying officials "have no reason to believe that the sexual encounter was consensual."
In New Mexico, according to attorneys and statutes, consensual sex between an adult and 17-year-old is not illegal. It's a crime if the adult is an authority figure and uses that "to coerce the child to submit." That's the statute officials allege Garcia violated.
The girl was a high school student, working with LCPD through the Las Cruces Public Schools' Excel program, the criminal complaint states. For decades, Excel has allowed high school juniors and seniors to gain first-hand career experience for elective credit. LCPS officials and LCPD counterparts have cut student ride-alongs indefinitely, they said. Administrators from both organizations said they planned to review -- and possibly revise -- related policies.
James Staley can be reached at 575-541-5476.


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I like the note that he's only been playing football for two years - sounds like we might have found a guy who is flying under the radar due to a lack of experience.
Welcome, Mr. Suttles! Wish the best and will be rooting for you as part of the Cyclone Family. Now lets get some more big fellas up front - Leath, Shortridge, Williston - whoever - and a couple solid LBs to be 'All In'!
I heard that Snooki, Pauly D and The Situation will each make $5 million for this seasons Jersey Shore. It just goes to show that if you put your mind to something and work hard, youre wasting your time. -- Jimmy Fallon
Here's the story with a few quotes. Cyclones add a big DE to recruiting class | News | Football | Cyclone Fanatic
Twitter: @ChrisMWilliams Facebook: Cyclone Fanatic
Really excited over our DL-prospects. The focus to get Big XII athletes in the program is clearly evident by the size - in particular the height of not just DL, but all players across the board - of those recruited by Rhoads, and in particular this class & last year's, too.
Can't teach size....welcome to Cyclone Nation !!!
Originally Posted by Cyclone27inQC Can't teach size....welcome to Cyclone Nation !!! That's what she said?
Welcome to Cyclone Nation!!
Originally Posted by Mr Janny 6'5 240. That's awesome size for a high school player. Right, and he can grow into that height; he could gain 20 lbs and still be quick, given his height. Considering that he is still learning the game, he could be a real force a couple of years or so down the road.
Great news! Hope we can afford to redshirt him--give him an extra year to learn/develop. I still think Irving could have benefitted from a redshirt.
Awesome! I am sure Ernest is going to thrive under Shane Burnham's tutelage.
"I'll eat up all your crackers and your licorice." -Humpty
looks like once Irving graduates we'll have a good replacement. Also BCS OFFER!!!!!
Fred's Fanatics- Member Fans of Fred Hoiberg and the 2013-2014 Iowa State Cyclones. Copy and Paste to Join. Denver Broncos fan: 13-3 Super Bowl Losers :( Arsenal Fan: 2nd place Iowa St: 20-5
Originally Posted by IHavNoCyCash looks like once Irving graduates we'll have a good replacement. Also BCS OFFER!!!!! I know it's not likely, but if he managed to play during Irving's senior year, our defensive ends would be 6'7" and 6'5". Those are some serious bookends to our Dline.
Coach Shane Burnham @ShaneBurnham52 Big day here in the Cyclone football offices....Really excited about the future of our front 4! #GetOffTheRock #NotYourFathersIowaState
Originally Posted by isuno1fan That's what she said? Nope, she can teach size.
Originally Posted by Judoka I like the note that he's only been playing football for two years - sounds like we might have found a guy who is flying under the radar due to a lack of experience. Exactly the pedigree of David Irving--hope he's as good an athlete! Originally Posted by ThatllDoCy Awesome! I am sure Ernest is going to thrive under Curtis Brays tutelage. Fixed that for ya. Coach Shane does DT's. Welcome aboard, Ernest!
Paul Rhoads' players never quit.
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What's New
NOW WITH OPENFEINT INTEGRATION!( Online worldwide leaderboards with OpenFeint - the largest social gaming network on the iPhone ).
App Description
Memory Planet is the best matching game on the app store!8 gorgeous themes, great graphics and super fun gameplay.
it's extremely addictive and challenging game, Play against the computer, or your friends !
there's also an Arcade Mode for endless fun.
NOW WITH OPENFEINT INTEGRATION! ( Online worldwide leaderboards with OpenFeint - the largest social gaming network on the iPhone ).
Features :
* Arcade mode & Classic mode.
* HEAD TO HEAD mode.
* Worldwide leaderboards with OpenFeint!
* 8 gorgeous themes.
* Simple yet challenging gameplay.
* Twitter & Facebook integration.
* Global Leaderboards.
With the Global Leaderboards, you'll able to see what is your global ranking.
it is also fully integrated with Twitter and Facebook so you could share your score with your friends, and even challenge them.
App Changes
July 29, 2010 Initial Release


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March 26, 2010 - 1:28pm
Uniesse 65 Sport: Playing For Keeps
, putting switches close to the skipper, engine panels in a second tier, and Raymarine displays just below ... , as evidenced by the dark-blue hull free of ripples, but there is also great forethought and engineering ... is impeccable.
Now, about the engines. This is where potential buyers of the Uniesse 65 Sport have ...
October 3, 2007 - 3:11pm
Uniesse 70
behind the helm console to port. My only complaint was that the Caterpillar electronic engine panels were ... engine choices include both MAN and Caterpillar from 1,300 to 1,570 hp. I liked having hydraulic power takeoffs fitted to both engines, giving a flexibility to power the various systems with just one engine ...
October 3, 2007 - 3:11pm
Uniesse 72 Motor Yacht
on a raised platform faces the burled-wood-and-leather-trimmed instrument panel. The engine and thruster ... and twin 20kW Kohler gensets.
Our test boat had the standard 1,300 hp MAN diesels; engines up 1,500 hp are optional. Access is a bit tight outboard between the fuel tanks and engines, but it's clear redundancy has ...
October 3, 2007 - 3:11pm
Uniesse 53
sound levels were indicative of an effort made to insulate the engines and exhausts. On the bridge, our sound meter registered little except wind and water: Even at full throttle, the engines were a distant ...
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1:49 pm
Tue January 29, 2013
NYS to Implement System to Diagnose Fiscal Stress
There's a new system ready to be put in place in New York State to help identify local governments and school districts under financial strain. The idea is to flag financial problems before they spiral into a crisis.
The New York State Comptroller's office has finalized plans to implement a statewide fiscal monitoring system to identify local governments and school districts under or nearing financial stress, by classifying their fiscal conditions. Brian Butry is a spokesman for State Comptroller Thomas DiNapoli.
Elliott Auerbach said he tested the system in the fall, during a 60-day comment period for local government and school-district officials, as well as officials from affiliated organizations. Auerbach is the Ulster County Comptroller, and former mayor of Ellenville.
He says the monitoring system is a valuable tool for municipalities.
New York State School Boards Association Spokesman David Albert says the system should be helpful in having an outside voice verify that a school district is in financial distress.
Comptroller DiNapoli will calculate and publicize an overall score of fiscal stress for about 2,300 municipalities and school districts.
That was Brian Butry, who says the comptroller's office will begin analyzing financial reports from municipalities whose fiscal year ended in December.
The New York State School Boards Association's David Albert says the fiscal monitoring system should be especially helpful in this economic environment.
He says key for his group was the comptroller offering services and solutions after finding a district to be under financial stress. Butry says Comptroller DiNapoli will offer municipal and school-district officials a number of services, such as helping to design safeguards; multi-year financial planning, and budget reviews.
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Jason Derulo - In My Head (Remix)
Artist: Jason Derulo
Featuring: Nicki Minaj
Producer: Jonathan "J.R." Rotem
Album: Jason Derulo
Avg Rating: 3.8 ( 60 total votes )
I know, I know, you had just begun to get Jason Derulo's hit single In My Head out of your, well, head, but there was no way we could let the song's official remix go by, especially when it features Nicki Minaj, the femcee everyone either loves or loves to hate. On the remix version J.R. Rotem's originally rock oriented production is tweaked slightly and given a softer, more electronic feel, while Jason retouches his vocals to essentially the same effect. And then, of course, there's the Nicki guest verse, which in true Minaj fashion includes some quasi-schizophrenic vocal stylings and off beat references. So now the question is clear: Did Nicki somehow manage to make In My Head even more memorable, or was the track catchier without her? Let the debate begin Booth. And for the four people out there who don't already know, the original version of In My Head can be found on the young crooner's self-titled album Jason Derulo, available now.
Listen to More: Jason Derulo , Nicki Minaj , Club Written by Nathan S.
Warner Bros. Records Inc.
First DJ Booth Appearance:
"Algebra" (2008)
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Ferguson, Mark E., Moritz Fleischmann, and Gilvan C. Souza
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Helm, Jonathan E., Shervin AhmadBeygi, and Mark P. Van Oyen
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Montoya, M., Anne P. Massey, and N. Lockwood
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Schoenherr, Tobias and Vincent A. Mabert
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Schoenherr, Tobias and Vincent A. Mabert
"An Exploratory Study of Procurement Strategies for multi-item RFQs in B2B Markets: Antecedents and Impact on Performance," Production and Operations Management 2010
Modi, Sachin and Vincent A. Mabert
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Souza, Gilvan C. and M. Ferguson
Closed-Loop Supply Chains: New Developments to Improve the Sustainability of Business Practices -
Blake, T., Anne P. Massey, Hillol Bala, and J. Cummings
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Khatri, Vijay and Carol V. Brown
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Mabert, Vincent A. and Michael J. Showalter
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Massey, Anne, Hillol Bala, T. Blake, and J. Cummings
"Driving health IT implementation success: Insights from The Christ Hospital," Business Horizons -
Montoya, M., Anne P. Massey, and Vijay Khatri
"Connecting IT service operations to service marketing practices: Trust in IT service providers," Journal of Management Info Systems -
Modi, Sachin and Vincent A. Mabert
"Exploring the Relationship between Efficient Supply Chain Management and Firm Innovation: An Archival Search and Analysis," Journal of Supply Chain Management -
Schoenherr, Tobias, Ditmar Hilpert, Ashok K. Soni, M.A. Venkataramanan, and Vincent A. Mabert
"Enterprise Systems Complexity and its Antecedents: A Grounded-Theory Approach," International Journal of Operations & Production Mgmt -
Koca, Eylem, Gilvan C. Souza, and Cheryl Druehl
"Managing Product Rollovers," Decision Sciences -
Denizel, Meltem, Mark Ferguson, and Gilvan C. Souza
"Multi-Period Remanufacturing Planning with Uncertain Quality of Inputs," IEEE Transactions on Engineering Management 2009
Aydin, Goker and S. Ziya
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Aydin, Goker and W. H. Hausman
"The Role of Slotting Fees in the Coordination of Assortment Decisions," Production and Operations Management -
Yang, Z., Goker Aydin, V. Babich, and D. Beil
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Cattani, Kyle and H. S. Heese
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De Vreede, G. J., R. O. Briggs, and Anne P. Massey
"Collaborative engineering: Foundations and opportunities," Journal of the Assoc for IS -
Mabert, Vincent A. and Kyle D. Cattani
"Supply Chain Design: Past, Present and Future," Production & Inventory Management Journal -
Mabert, Vincent A.
"Objectives and Future Directions of APICS' Production & Inventory Management Journal," Production & Inventory Management Journal -
Mabert, Vincent, Ashok K. Soni, M. A. Venkataramanan, and Tobias Schoenherr
"Enterprise System (ES) Implementations in German Manufacturing SMEs: Observations from Eight Case Studies," Handbook of Research in Enterprise Systems -
Tiwari, V., J. H. Patterson, and V. Mabert
"Scheduling Projects with Heterogeneous Resources to Meet Time and Quality Objectives," European Journal of Operational Research -
Mahar, S., Kurt M. Bretthauer, and M. A. Venkataramanan
"The Value of Virtual Pooling in Dual Sales Channel Supply Chains," European Journal of Operational Research -
Montoya, M., Anne P. Massey, C. Hung, and C. Crisp
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Ferguson, Mark, V. Daniel Guide, Jr., Eylem Koca, and Gilvan C. Souza
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Albright, S. Christian and Wayne Winston
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Data Analysis and Decision Making (Revised 3rd Edition) -
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Aydin, Goker and S. Ziya
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Blocher, J. D. and D. Chhajed
"Minimizing Customer Order Lead - Time in a Two - Stage Assembly Supply Chain," Annals of Operations Research -
Blocher, J. D., S. P. Choi, and S. Gavirneni
"Value of Sharing Production Yield Information in a Serial Supply Chain," Production and Operations Management -
Schoenherr, T. and V. Mabert
"The Use of Bundling in B2B Online Reverse Auctions," Journal of Operations Management -
Brown, S., V. Venkatesh, J. Kuruzovich, and Anne P. Massey
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"Bundling for Online Reverse Auctions: Approaches and Experiences," Best Practices in Online Procurement Auctions -
Watts, C., V. Mabert, and N. Hartman
"Supply Chain Bolt-ons: Investment and Usage by Manufacturers," International Journal of Operations & Production Mgmt


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