also under the control of deacetylation via HDAC, and HDAC3 is the mediator of this process both in vivo and in vitro. Methylation Methylation of lysine 218 and 221 together or lysine 37 alone in the RHD domain of RELA can lead to increased response to cytokines such as IL-1 in mammalian cell culture. Interactions As the prototypical heterodimer complex member of the NF-κB, together with p50, RELA/p65 interacts with various proteins in both the cytoplasm and in the nucleus during the process of classical NF-κB activation and nuclear translocation. In the inactive state, RELA/p50 complex is mainly sequestered by IκBα in the cytosol. TNFα, LPS and other factors serve as activation inducers, followed by phosphorylation at residue 32 and 36 of IκBα, leading to rapid degradation of IκBα via the ubiquitin-proteasomal system and subsequent release of RELA/p50 complex. RELA nuclear localization signal used to be sequestered by IκBα is now exposed, and rapid translocation of the NF-κB occurs. In parallel, there is a non-classical NF-κB activation pathway involving the proteolytic cleavage of p100 into p52 instead of p50. This process does not require RELA, hence will not be discussed in detail here. After NF-κB nuclear localization due to TNFα stimulation, p50/RELA heterodimer will function as a transcription factor and bind to a variety of genes involved in all kinds of biological processes, such as leukocyte activation/chemotaxis, negative regulation of TNFIKK pathway, cellular metabolism, antigen processing, just to name a few . Phosphorylation of RELA at different residues also enables its interaction with CDKs and P-TEFb. Phosphorylation at serine 276 in RELA allows its interaction with P-TEFb containing CDK9 and cyclin T1 subunits, and phospho-ser276 RELA-P-TEFb complex is necessary for IL-8 and Gro-β activation. Another mechanism is involved in the activation of genes preloaded with Pol II in a RELA serine 276 phosphorylation independent manner. RELA has been shown to interact with: APBA2, AHR, ASCC3, BRCA1, BTRC, c-Fos, c-Jun, C22orf25, CDK9, CEBPB, CEBPE, CREBBP, CSNK2A1, CSNK2A2, DHX9, EP300, ETHE1, FUS, GCN5, HDAC1, HDAC2, HDAC3, ING4, IκBα, KLF5, MDM2, MEN1, MSK1, MTPN, NCF1, NFKB1, NFKB2, NFKBIB, NFKBIE, NR3C1, NCOR2, PARP1, PDLIM2, PIAS3, PIM1, PIN1, PKA, POU2F1, PPARG, PPP1R13L, PRKCZ, REL, RFC1, RNF25, SIRT1, SOCS1, SP1, STAT3, TAF4B, TBP, TP53, and TRIB3. Role in immune system Gene knockout of NF-κB genes via homologous recombination in mice showed the role of these components in innate and adaptive immune responses. RELA knockout mice is