phagocytes fight pathogens using canonical and noncanonical autophagy pathways ( codogno et  al . , 2011 ) . also known as lc3-associated phagocytosis ( lap ) , this form of noncanonical autophagy is a unique pathway that links signaling during phagocytosis with optimal degradation of the phagocytosed cargo via recruitment of the lc3-pe conjugation system required for lysosomal fusion and maturation of the laposome ( mehta et  al . , 2014 ) . lap , but not canonical autophagy , plays a critical role in the degradation of engulfed aspergillus conidia ( akoumianaki et  al . , 2016 , , 2015b , kyrmizi et  al . , 2013 , ma et  al . , 2012 , martinez et  al . , 2015 ) . these mice , however , also exhibited increased pathological inflammation and pro - inflammatory cytokine levels . thus , as observed in murine and human chronic granulomatous disease ( cgd ) , in which lap is defective ( de luca et  al . , 2014 ) , the inflammation and infectious susceptibility are all regulated by lap . by allowing efficient pathogen clearance and/or degradation of inflammatory mediators ( lapaquette et  al . , 2015 ) , cassettes of autophagy proteins may play a broad role in cellular and immune homeostasis ( subramani and malhotra , 2013 ) . indeed , defects in autophagic machinery have been linked with aberrant host defense and inflammatory diseases ( lapaquette et  al . , 2015 , levine et  al . , 2011 , netea - maier et  al . , 2016 ) . for lap , in particular , emerging evidence suggests that this pathway also regulates , among others ( mehta et  al . , 2014 ) , dead cell clearance and inflammation  ( martinez et  al . , 2016 ) . thus , understanding the molecular mechanisms underlying lap ability to modulate the inflammatory response during autophagy may have therapeutic implications . ifn- is an essential cytokine in the protective host response against fungi ( romani , 2011 ) and has been implicated as a treatment option in invasive fungal infections ( delsing et  al . , 2014 , dignani et  al . , 2005 ) . in addition to its immunometabolic activity ( cheng et  al . , 2016 , romani et  al . , 2008 ) ( al - zeer et  al . , 2009 , gutierrez et  al . , 2004 ) via recruitment of immunity - related gtpase ( al - zeer et  al . , 2009 , gutierrez et  al . , 2004 , kim et  al . , 2011 , singh et  al . , 2006 ) as well as the death - associated protein kinase 1 ( dapk1 ) ( gade et  al . , 2012 ) . dapk1 is a cell death - inducing ca / calmodulin - regulated serine / threonine kinase , originally identified as an activator of ifn--induced cell death ( gozuacik et  al . , 2008 ) . dapk1-induced expression by ifn- occurs through the transcription factor c / ebp- in association with the key endoplasmic reticulum ( er ) stress - activated transcription factor , atf6 ( gade et  al . , 2012 , recent findings have highlighted additional roles of this kinase beyond cell death ( lin et  al . , 2010 ) that include a negative regulation of inflammation ( lai and chen , 2014 ) and attenuation of a variety of inflammatory responses in lung and airway injury ( nakav et  al . , 2012 ) . thus , dapk1 could be an attractive player in the regulation of the inflammatory response during the process of fungal clearance initiated by ifn-. in the present study , we have evaluated whether dapk1 may contribute to dampening the inflammatory response during fungal lap . to this purpose , we have resorted to a combination of basic and translational approaches involving selected deficient mice as well as human immunodeficiencies to establish that the atf6/c / ebp-/dapk1 axis activated by ifn- not only mediates lap to a.  fumigatus but also regulates nod - like receptor protein 3 ( nlrp3 ) activation during infection . genetic or functional dapk1 deficiency increased inflammation and susceptibility to aspergillosis in high - risk patients . however , dapk1 activity could be restored by ifn-. thus , recognizing specific autophagy hallmarks triggered during infection may provide important insights into how autophagy and inflammation are integrated and reciprocally regulated to provide the optimal fungal clearance in the relative absence of immunopathology . in order to evaluate whether dapk1 is induced in response to a.  fumigatus , we monitored dapk1 expression by rt - pcr , immunoblotting , and immunofluorescence staining either in  vitro in raw264.7 cells exposed to live conidia or in  vivo in mice intranasally infected with the fungus . dapk1 gene ( figure  1a ) and protein ( figures 1b and 1c ) expression was greatly upregulated at 46  hr of exposure to conidia , remained elevated till 1012  hr , and declined thereafter . germination of the fungus appeared to be required for dapk1 expression to occur , being maximally induced by swollen conidia ( figure  1d ) . in  vivo , dapk1 gene ( figure  1e ) and protein ( figure  1f ) expression was increased during the first week of the infection in c57bl/6 mice . consistent with the observation that dapk1 is induced by ifn- ( gade et  al . , 2012 ) , ifn- exposure significantly enhanced dapk1 expression in raw264.7 cells ( figures 1a1c ) , and dapk1 expression was defective in ifng mice in  vivo ( figures 1e and 1f ) and ifng macrophages in  vitro ( figure  1 g ) . of interest , exogenous ifn- restored dapk1 expression in ifn- deficiency in  vivo ( figures 1e and 1f ) and in  vitro ( figure  1 g ) , a finding suggesting that signaling through the ifn receptor is required for dapk1 activation . because innate and non - innate cells are capable of producing ifn- in response to fungi ( romani , 2011 ) , a paracrine action on myeloid cells for dapk1 induction is likely . however , upon looking for ifn- expression and production by macrophages in response to the fungus , we found that ifn- gene expression increased in more than 85% of raw264.7 cells after fungal exposure ( figure  2a ) and was paralleled by increased protein production , as revealed by immunofluorescence ( figure  2b ) and immunoblotting ( figure  2c ) . the production of ifn- was functional , as evidenced by the upregulated expression of ip10 gene ( figure  2f ) , and occurred in response to dectin-1 and myd88 signaling ( figures 2 g and 2h ) via nf - kb ( figure  2i ) . because dapk1 expression paralleled that of ifn- ( figures 2j and 2k ) , these results suggest that ifn- production upon dectin-1/myd88 recognition of the fungus may autocrinally activate dapk1 in phagocytic cells . the transcription factor c / ebp- regulates transcription of dapk1 in response to ifn- , in collaboration with atf6 , a key er stress - activated transcription factor ( gade et  al . , 2012 , er stress causes dissociation of atf6 from its inhibitor , allowing its translocation from the er membrane to the golgi apparatus , where site - specific endoproteolysis generates transcriptionally active atf6 , permitting its nuclear entry and target gene regulation ( shen and prywes , 2005 ) . to evaluate the involvement of atf6 and c / ebp- in ifn--dependent dapk1 activation , we assessed atf6 cleavage and c / ebp- phosphorylation in raw264.7 stimulated with ifn- and exposed to swollen conidia . similar to tunicamycin , used as positive control ( kozutsumi et  al . , 1988 ) , the cleaved form of atf6 was observed upon stimulation and was enhanced by ifn- , as revealed by immunoblotting ( figure  s1a , available online ) , immunofluorescence staining ( figure  s1b ) , and nuclear translocation ( figure  s1c ) . conidia also activated c / ebp- phosphorylation ( figure  s1d ) and its nuclear translocation ( figure  s1e ) , an activity potentiated by ifn-. all together , these results demonstrated that a.  fumigatus conidia activated the ifn--atf6-c / ebp-/dapk1 pathway . increased accumulation of the autophagy marker gfp - lc3 in  punctae representing the autophagosome membrane has been reported upon dapk1 expression ( levin - salomon et  al . , 2014 ) . to evaluate the contribution of dapk1 to a.  fumigatus - induced lap , we measured the lc3 punctae and the lc3b - ii / lc3b - i ratio in raw264.7 cells transiently transfected with the egfp - lc3 plasmid , pulsed with swollen conidia , and depleted of dapk1 by means of small interfering rna ( sirna ) or a chemical inhibitor . in line with previous observations ( de luca et  al . 2013 ) , the number of cells with punctate dots containing egfp - lc3 increased ( figures 3a and 3b ) upon phagocytosis of the fungus and was dependent on dapk1 , as did the ratio of lc3-ii to lc3-i ( figure  3c ) . not only did dapk1 co - localize with lc3 in phagosomes containing conidia in more than 80% of cells , but not inert beads , which do not activate lap ( martinez et  al . , 2015 , sanjuan et  al . , 2007 ) ( figure  3d ) , but its functional inhibition , while not affecting fungal phagocytosis ( data not shown ) , also decreased the number of lc3 punctae and the lc3b - ii / lc3b - i ratio ( figures 3a3c ) . the involvement of dapk1 appeared to be selective for lap , as dapk1 co - localized with the lap components rubicon , beclin-1 , and atg7 ( martinez et  al . , 2015 , sanjuan et  al . , 2007 ) upon phagocytosis of conidia , but not beads , as revealed by cell immunofluorescence staining ( figures 3d and s2 ) and immunoblotting of  purified phagosomes ( figures 3e and 3f ) . consistent with the requirement of nox2 for lap ( martinez et  al . , 2015 ) , silencing of rubicon and nox2 , in addition to beclin-1 and atg7 , with specific sirna abrogated dapk1 's recruitment on phagosomes  ( figures 3 g and s6 ) , suggesting that retention of dapk1 on aspergillus - containing phagosomes depends on the essential lap protein rubicon and additional autophagy proteins . confirming the involvement of dapk1 in lap to the fungus , dapk1 inhibition did not affect rapamycin - induced autophagy ( figures s3a and s3b ) , a finding confirming that dapk1 is not involved in starvation - induced autophagy ( gozuacik and kimchi , 2006 ) . this finding is important , given that ifn- could activate autophagy through tryptophan starvation via the indoleamine 2,3-dioxygenase ( ido)1 enzyme ( metz et  al . , 2012 ) . in this regard , we found that ifn--induced autophagy was defective in indo macrophages and not modified by the dapk1 inhibitor ( figure  s3c ) . in contrast , lc3-dependendent phagocytosis of  the fungus was observed in indo macrophages in  vitro ( figure  s3d ) , and dapk1 expression increased in indo mice upon infection in  vivo ( figure  s3e ) . blocking dapk1 greatly increased the fungal burden and the dissemination in infected indo mice ( figure  s3f ) , as well as the inflammatory cell recruitment in the lung and the bronchoalveolar lavage fluid ( figures s3 g and s3h ) , a finding indicating that the starvation - induced autophagy and lap are distinct , yet complementary , pathways in fungal clearance . altogether , these results point to dapk1 as an important effector molecule mediating ifn--dependent lap and the ensuing fungal clearance . these results were corroborated by strong acidification ( figure  4a ) and lamp-1 ( lysosomal - associated membrane protein  1 ) positivity ( figure  4b ) in conidia - containing vacuoles , indicating fusion with lysosomes . interestingly , and quite surprisingly , both acidification and lamp-1 positivity were unaffected , if not increased , upon dapk1 inhibition ( figures 4a and 4b ) , a finding suggesting that the lysosomal degradative pathway of fungal clearance was relatively independent from dapk1 . the ubiquitin- and adaptor p62-dependent autophagic targeting of damaged membranes that occurs during pathogen phagocytosis has been shown to help to control detrimental downstream signaling during bacterial invasion into host cells ( choi et  al . , 2014 , given the pleiotropic cellular effects of dapk1 beyond kinase activity ( lin et  al . , 2010 ) , which include degradation through ankyrin repeats ( shiloh et  al . , 2014 ) , we tested whether dapk1 could control the activation of the proteasomal degradation pathway during fungal clearance . we have recently found that this pathway crucially regulates nlrp3 inflammasome activity in response to the fungus that serves to curb inflammation ( iannitti et  al . , 2016 ) . we found decreased cellular ubiquitination ( figure  4c ) , increased p62 expression ( figures 4d and 4e ) , and proteasomal degradation ( figure  4f ) upon inhibition of dapk1 in raw264.7 cells or ex  vivo phagocytes exposed to conidia in the presence of ifn- , a finding suggesting that the ubiquitin / proteasomal pathway is activated during fungal lap and that dapk1 is an active player . we looked therefore for nlrp3 expression and activity in raw264.7 cells exposed to the fungus in  vitro as well as in infection in  vivo upon dapk1 inhibition . we found that nlrp3 expression and caspase-1 cleavage were increased in  vitro ( figures 5a and 5b ) . ubiquitin - mediated proteasomal processing of  nlrp3 involves the fbxo3 e3 ligase component that targets fbxl2 , which robustly catalyzes nlrp3 ubiquitination ( han et  al . , 2015 ) . the increased nlrp3 activity upon dapk1 inhibition correlated with decreased nlrp3 ubiquitination ( figures 5c and s4 ) and decreased binding of fbxl2 to nlrp3 ( figure  5d ) . in  vivo , dapk1 inhibition with the chemical inhibitor or  sirna ( figures s5 and s6 ) was associated with increased nlrp3 expression ( figure  5e ) , caspase-1 cleavage ( figure  5f ) , il-1/il-18 production and mpo expression ( figure  5 g ) , increased fungal load ( figure  5h ) , and tissue inflammation ( figure  5i ) , likely due to defective autophagy ( figure  5j ) . these effects were not observed in nlrp3 mice treated with the dapk1 inhibitor ( figures 5k and 5l ) , confirming that nlrp3 mediates the downstream effects on inflammation of dapk1 . despite the ability of dapk1 to regulate cell apoptosis via bcl-2 expression ( akar et  al . , 2008 ) , these findings indicate that dapk1 activation during lap may restrain pathogenic nlrp3 activity in response to the fungus , likely impacting local inflammation . the above results prompted us to evaluate whether the ability of ifn- to activate dapk1 could be therapeutically exploited . to this purpose , we assessed dapk1 expression and its modulation by ifn- in murine and human cgd , in which both defective autophagy and increased inflammasome activity have been described ( de luca et  al . , 2014 ) . dapk1 gene and protein expression was defective in p47 infected mice ( figures 6a and 6b ) and in  vitro in both p47 lung macrophages ( figures 6c6e ) and monocytes from cgd patients ( figure  6f ) . ifn- protein expression ( figure  6 g ) and production ( figure  6h ) were also defective in cgd cells , a finding indicating that reactive oxygen species ( ros ) are upstream signals for ifn- induction . of great interest , treatment with ifn- restored dapk1 expression ( figures 6a and 6b ) , reduced the fungal growth ( figure  6i ) , and decreased il-1 production ( figure  6j ) in infection . similarly , in  vitro , ifn- restored dapk1 expression ( from < 5% to up 90% double positive cells after treatment ) ( figures 6c6e ) and decreased inflammation in murine ( figure  6k ) and human cgd mononuclear cells ( figures 6f , 6l , and 6 m ) , a finding suggesting the drugability of dapk1 in cgd by ifn- therapy . incidentally , our unpublished observations suggest that anakinra , known to decrease nlrp3 activity and restore lap in both murine and human cgd cells ( de luca et  al . , 2014 ) although aspergillosis remains a major cause of morbidity and mortality in cgd patients ( marciano et  al . , 2015 ) , it is a much more common problem in hematopoietic stem cell transplantation ( hsct ) patients ( harrison et  al . , 2015 ) . we therefore assessed the impact of dapk1 in this setting by analyzing five dapk1 snps in a cohort of hsct patients . in the univariate analysis , applying a general genetic model , none of the dapk1 snps significantly associated with an increased incidence of infection , either in recipients or in donors ( table s1 ) . however , the dapk1 rs1964911 snp , located on the promoter region , showed a trend for association in recipients ( p  = 0.066 ) . indeed , by testing the association of rs1964911 using a recessive genetic model , the c / c genotype turned out to be significantly associated with an increased incidence of aspergillosis in recipients ( 30.2% for c / c and 16.2% for a carriers , p  = 0.029 ) ( figure  7a ) , but not in donors ( 24.2% for c / c and 16.7% for a carriers , p  = 0.219 ) . the analysis of dapk1 rs1964911 recessive recipient / donor combination further confirmed the effect of c / c genotype in increasing the risk of infection , especially when present simultaneously in both recipients and donors ( 42.1% for c / c pairs versus 17.4% for a carriers pairs , p  = 0.029 ) the association of c / c genotype with increased risk of infection remained statistically significant after adjusting for hla - matching status , underlying disease , and antifungal prophylaxis ( donors , rr  = 1.873 , p  = 0.036 ; donors / recipients combined , rr  = 2.184 , p  = 0.027 ) . functional studies in  vitro revealed that both dapk1 gene ( figure  7c ) and protein ( figures 7d and 7e ) were defective in peripheral mononuclear cells from patients with the c / c genotype , while nlrp3 expression ( figure  7f ) and il-1 production ( figure  7 g ) were increased . thus , genetic deficiency of dapk1 may contribute to the risk of invasive aspergillosis in hsct patients . the results of the present study identify a host defense pathway controlled by ifn- signaling . we found that ifn- not only mediated lap to a.  fumigatus but also regulated nlrp3 activation during infection . the importance of lap for fungal clearance ( kyrmizi et  al . , 2013 , martinez et  al . , 2015 , 2016 ) and its subversion by fungal melanin ( akoumianaki et  al . , 2016 ) have been recently described . however , inflammation has to be controlled under microbial autophagy in the lung to prevent pulmonary overreaction ( kanayama et  al . , 2015a ) . the dapk1 interactome has shown that dapk1 , by participating in several signaling cascades by means of its catalytic activity and protein - protein interactions ( bialik and kimchi , 2014 ) , mediates various cellular effects . this may explain the complex role of dapk1 in the regulation of inflammation , which is likely dependent on cell types and environment ( lai and chen , 2014 ) . indeed , while dapk1 deficiency attenuated inflammasome - induced peritonitis ( chuang et  al . , 2011 ) , it increased lps - induced inflammation in the lung , an activity dependent upon its inflammation - suppressive functions rather than the prevention of the inflammatory cell recruitment ( nakav et  al . , 2012 ) . consistently , dapk1 was shown to activate the translational silencing of various inflammatory genes in response to ifn- ( mukhopadhyay et  al . , 2008 ) . our study expands upon the molecular mechanisms by which dapk1 regulates the inflammatory response in the lung by showing that it inhibits nlrp3 activity by promoting its proteasomal degradation via fbxl2 , as reported ( han et  al . , 2015 ) . this finding is only apparently in contrast with what was observed in 293 t cells , where dapk1 served a structural role in the assembly of the nlrp3 inflammasome ( chuang et  al . , 2011 ) . indeed , the dapk1 requirement for nlrp3 activation was stimulus dependent ; nlrp3 activity was ablated upon dapk deficiency in response to tlr2 and tlr7 , but not tlr4 signaling ( chuang et  al . , 2011 ) . as a matter of fact , lps - induced intestinal inflammation was increased in dapk1 deficiency in mice ( nakav et  al . , 2012 ) and humans where enhanced severity of gut inflammation and ulcerative colitis was observed ( kuester et  al . , 2010 ) . promotion of nlrp3 activity was meant to contribute to dapk1-induced cell death ( chuang et  al . , 2011 ) , an activity that we have not seen in the lung . therefore , dapk1 activation initiated by ifn- may serve a unique role in the lung by tightly regulating inflammasome activity during fungal lap through a mechanism that is shared with autophagy ( shi et  al . , 2012 ) . the ubiquitin - proteasomal pathway appeared to be involved in  this process , for both cellular ubiquitination and adaptor p62  expression were decreased or increased , respectively , after dapk1 inhibition . that the ubiquitin - like conjugation system of the autophagy pathway , but not the canonical degradative autophagy process , is required for ifn--induced lap in intracellular infection has been reported ( choi et  al . , 2014 ) . interestingly , we  have found that conidia may undergo ubiquitination during phagocytosis ( figure  4a ) , a finding suggesting the occurrence of xenophagy , a process that targets intravacuolar microbes for ubiquitination followed by recruitment of , among others , p62 adaptor protein and lc3 , and leading to autophagosome fusion with lysosomes for degradation ( choi et  al . , 2014 , deretic et  al . , 2013 ) . in this regard , we have already shown that inhibitors of both the lysosomal and proteasomal pathways negatively affected the ability of phagocytes to control intracellular fungal growth ( iannitti et  al . , 2016 ) . precisely how the ubiquitin - proteasomal degradative pathway is activated by dapk1 to inhibit nlrp3 , and whether the activation of the immunoproteasome by ifn- ( aki et  al . , 1994 ) it is nevertheless of interest that the ankyrin repeats of dapk1 may bind e3 ubiquitin ligases ( jin et  al . , 2002 ) and that the immunoproteasome is implicated in fungal pathogenicity ( mundt et  al . , 2016 ) and lung responses to infections ( keller et  al . , 2015 ) . ifn- , produced by innate and adaptive lymphocytes , plays a critical role in mediating protection against fungi ( romani , 2011 ) . the results of the present study show that macrophages are alternative sources of ifn- produced upon dectin-1/myd88 stimulation and ros signaling , a finding suggesting that early production of ifn- by macrophages may occur in the relative absence of innate or adaptive immune cells and , as such , be exploitable in selected immunodeficiencies . combined with antifungal drug therapy , immunotherapy with ifn- represents a treatment option in patients at risk for fungal infections ( the international chronic granulomatous disease cooperative study group , 1991 , armstrong - james et  al . , 2010 , bodasing et  al . , 2002 , delsing et  al . , 2014 , dignani et  al . , 2005 , stevens et  al . , 2006 ) . the results of the present study increase our understanding of the immunopharmacology of ifn- in infection treatment that now includes an activity on dapk1 . this may have therapeutic implications given that dapk expression and activity are deregulated in a variety of diseases including cancer ( li et  al . we have found that dapk1 activity was defective in cgd but restored by ifn-. we have also found that genetic dapk1 deficiency increased inflammation and susceptibility of hsct patients to aspergillosis . these findings , while reinforcing the therapeutic utility of ifn- in human cgd , also suggest a possible ifn- recommendation in transplanted patients . in conclusion , it appears that ifn- , through its multitasking activity encompassing immune tolerance via the ido1 pathway ( romani et  al . , 2008 ) , immunometabolic activity ( cheng et  al . 2012 ) , and , now , optimal microbial clearance through the dapk1-lap pathway , fulfills the requirement of an ideal candidate player at the host - fungi interface . mice , 810  weeks old , were purchased from charles river or bred at the animal facility of perugia . for infection a  total of 20,000  u / mouse ifn- was given daily starting the day of the infection until the sacrifice . dapk inhibitor was administered intranasally at the dose of 500  g / kg for 5  days starting 3  days before the infection . for dapk1 raw264.7 and raw - gfp - lc3 cells were grown in supplemented rpmi medium as described ( de luca et  al . , 2012 ) . cells were pretreated overnight with 200  u / ml rifn- before pulsing with a.  fumigatus resting or swollen conidia . for dapk1 inhibition , cells were pretreated with 3  m dapk inhibitor as described ( usui et  al . , 2012 ) . sn50 was used at 18  m for 1  hr before a.  fumigatus pulsing . for in  vitro silencing , cells were transfected with 40  nm specific sirnas before a.  fumigatus or inert bead stimulation . for immunoprecipitation , the lysates were incubated with anti - ubiquitin , anti - fbxl2 antibody , and protein g sepharose beads . for immunoblotting , the lysates were incubated with the following antibodies : dap kinase 1 , atf6 ; c / ebp and p - c / ebp , lc3b , sqstm1/p62 , fbxl2 , ha , ubiquitin , caspase-1 p10 , ifn- , lamin b1 , nlrp3 , and caspase-1 . phagosomes from raw264.7 cells were obtained as described ( martinez et  al . , 2015 ) and the proteins were probed with dap kinase 1 , lc3b , beclin-1 , rubicon , and atg7 . cytokines in lung homogenates or cell culture supernatants was determined by specific elisas ( r&d systems ) . real - time rt - pcr was performed using sybr green chemistry ( biorad ) . fixed cells were incubated with dapk1 , atf6 , c / ebp , p - c / ebp , ifn- , lc3b , sqstm1/p62 , lamp1 , nlrp3 , and ubiquitin antibodies . acridine orange was used to detect the cellular acidic compartment by measuring the red fluorescence emission . monocytes were isolated from peripheral blood mononuclear cells ( pbmcs ) of healthy donors or two cgd patients , harboring the mutations c.736c > t , p.q246x and whole cybb gene deletion ( 69.84 kb ) . cells were cultured for 4  hr with live a.  fumigatus conidia in the presence of 200  u / ml rifn- before assays . the genetic study included 277 patients undergoing allogeneic hsct and their respective donors ( who were related in 98% of cases ) . five dapk1 snps complied with the selection criteria : rs1964911 , rs4878104 , rs4877365 , rs7025760 , and rs1056719 . p values were calculated by a one - way anova ( bonferroni s post hoc test ) . for single comparison , the probability of ia according to dapk1 variants was determined with the use of the cumulative incidence method , and dapk1 status among patients with and without infection was compared with the use of gray s test . performed most of the in  vitro experiments ; m.b . performed murine in  vivo experiments ; m. pariano performed some immunofluorescence experiments ; m. puccetti and c.g .
summarydefects in a form of noncanonical autophagy , known as lc3-associated phagocytosis ( lap ) , lead to increased inflammatory pathology during fungal infection . 
 although lap contributes to fungal degradation , the molecular mechanisms underlying lap - mediated modulation of inflammation are unknown . 
 we describe a mechanism by which inflammation is regulated during lap through the death - associated protein kinase 1 ( dapk1 ) . 
 the atf6/c / ebp-/dapk1 axis activated by ifn- not only mediates lap to aspergillus fumigatus but also concomitantly inhibits nod - like receptor protein 3 ( nlrp3 ) activation  and restrains pathogenic inflammation . in mouse models and patient samples of chronic granulomatous disease , 
 which exhibit defective autophagy and  increased inflammasome activity , ifn- restores reduced dapk1 activity and dampens fungal growth . 
 additionally , in a cohort of hematopoietic stem cell - transplanted patients , a genetic dapk1 deficiency is associated with increased inflammation and heightened aspergillosis susceptibility . 
 thus , dapk1 is a potential drugable player in regulating the inflammatory response during fungal clearance initiated by ifn-.