Ser396

Site Information
NtVDLHIsNsHPLsL SwissProt Entrez-Gene
Blast this site against: NCBI SwissProt PDB
Site Group ID: 449028

In vivo Characterization
Methods used to characterize site in vivo:	electrophoretic mobility shift ( 36 , 38 ) , immunoassay ( 5 ) , immunoprecipitation ( 11 , 13 , 21 , 27 ) , mass spectrometry ( 11 , 23 , 25 ) , mass spectrometry (in vitro) ( 23 ) , mutation of modification site ( 3 , 11 , 12 , 13 , 16 , 23 , 27 , 30 , 32 , 36 , 38 ) , phospho-antibody ( 2 , 4 , 5 , 6 , 7 , 9 , 13 , 14 , 15 , 17 , 18 , 19 , 20 , 21 , 22 , 24 , 26 , 29 , 31 , 32 , 33 , 36 ) , western blotting ( 2 , 4 , 5 , 6 , 7 , 9 , 11 , 13 , 14 , 15 , 17 , 18 , 19 , 20 , 21 , 22 , 24 , 26 , 27 , 29 , 31 , 32 , 33 )
Disease tissue studied:	brain cancer ( 29 ) , glioblastoma ( 29 ) , glioblastoma multiforme ( 29 ) , glioma ( 29 ) , breast cancer ( 2 , 3 , 21 ) , lung cancer ( 4 , 20 , 24 ) , non-small cell lung cancer ( 4 , 20 ) , non-small cell lung adenocarcinoma ( 4 , 20 ) , fibrosarcoma of soft tissue ( 2 , 9 )
Relevant cell line - cell type - tissue:	293 (epithelial) ( 13 , 16 , 18 , 22 , 23 , 26 , 32 , 33 , 36 , 38 ) , A549 (pulmonary) ( 4 , 20 , 24 ) , CD4+ (T lymphocyte) ( 17 ) , COS (fibroblast) ( 38 ) , E.coli (bacterial) [IKKE (human), transfection] ( 25 ) , fibroblast-skin ( 5 ) , HEC-1B (endometrial) ( 36 ) , HEK293T (epithelial) ( 6 , 11 , 12 , 19 , 20 , 27 ) , HeLa (cervical) ( 7 , 14 , 30 ) , HT1080 (fibroblast) ( 2 , 9 ) , macrophage-bone marrow ( 6 ) , MCF-7 (breast cell) ( 3 ) , MDA-MB-453 (breast cell) ( 2 , 21 ) , MEF (fibroblast) ( 6 , 15 , 31 ) , mononuclear ( 29 ) , U-937 (myeloid) ( 36 ) , U373 MG (glial) [CD14 (human), transfection] ( 29 ) , U373 MG (glial) ( 36 )

Upstream Regulation
Regulatory protein:	DDAH2 (human) ( 6 ) , DDX3 (human) ( 20 ) , DDX58 (human) ( 26 , 33 ) , EGFR (human) ( 21 ) , GSK3B (human) ( 22 ) , IFI35 (human) ( 18 ) , IKKE (human) ( 24 ) , MAVS (human) ( 26 ) , MST1 (human) ( 13 ) , RALB (human) ( 19 ) , ROBO3 (human) ( 14 ) , TBK1 (human) ( 24 , 26 , 33 ) , TFG (human) ( 7 ) , TICAM1 (human) ( 33 ) , TNFAIP3 (human) ( 33 ) , TRIAD3 (human) ( 26 )
Putative in vivo kinases:	IKKB (human) ( 27 ) , IKKE (human) ( 25 ) , TBK1 (human) ( 2 , 7 , 27 )
Kinases, in vitro:	IKKE (human) ( 30 , 34 ) , TBK1 (human) ( 23 , 30 , 34 )
Treatments:	1400W ( 6 ) , anti-CD3/CD28 ( 17 ) , argimesna ( 6 ) , Auranofin ( 2 ) , CpG ( 37 ) , dexamethasone ( 29 ) , double-stranded_RNA ( 36 ) , dsDNA ( 9 ) , HBSS ( 2 ) , ISD ( 6 ) , KU-0063794 ( 7 ) , Lipofectamine ( 2 ) , lncRNAs ( 4 ) , LPS ( 6 , 29 , 32 ) , Mdivi-1 ( 6 ) , poly(dA:dT) ( 10 ) , poly(I-C) ( 2 , 6 , 17 , 19 , 29 , 31 , 32 ) , RO-3306 ( 9 ) , siRNA ( 7 ) , virus infection ( 4 , 5 , 6 , 7 , 20 , 22 , 23 , 24 , 30 , 31 , 36 , 38 )

Downstream Regulation
Effects of modification on IRF3:	activity, induced ( 5 , 10 , 30 , 36 ) , activity, inhibited ( 18 ) , enzymatic activity, induced ( 20 ) , intracellular localization ( 30 , 38 ) , molecular association, regulation ( 3 , 7 , 23 , 28 , 30 , 35 , 38 ) , protein conformation ( 15 ) , protein degradation ( 30 )
Effects of modification on biological processes:	apoptosis, induced ( 2 ) , transcription, altered ( 27 , 36 ) , transcription, induced ( 2 , 3 , 4 , 5 , 6 , 7 , 10 , 12 , 16 )
Induce interaction with:	CBP (human) ( 23 , 28 , 30 , 38 ) , DNA ( 3 ) , IRF3 (human) ( 7 , 28 , 30 , 35 )

References
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2	Glanz A, et al. (2021) Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities. J Biol Chem 297, 101274 34619149 Curated Info
3	Vedagiri D, et al. (2021) Retinoic Acid Inducible Gene-I like Receptors Activate Snail to Limit RNA Viral Infections. J Virol, JVI0121621 34379517 Curated Info
4	Lai C, et al. (2021) Long noncoding RNA AVAN promotes antiviral innate immunity by interacting with TRIM25 and enhancing the transcription of FOXO3a. Cell Death Differ 33990776 Curated Info
5	Krump NA, et al. (2021) Merkel cell polyomavirus infection induces an antiviral innate immune response in human dermal fibroblasts. J Virol 33883226 Curated Info
6	Huang S, et al. (2021) DDAH2 suppresses RLR-MAVS-mediated innate antiviral immunity by stimulating nitric oxide-activated, Drp1-induced mitochondrial fission. Sci Signal 14 33850055 Curated Info
7	Khan KA, et al. (2021) TRK-Fused Gene (TFG), a protein involved in protein secretion pathways, is an essential component of the antiviral innate immune response. PLoS Pathog 17, e1009111 33411856 Curated Info
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9	Zhong L, et al. (2020) Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis. Cell Discov 6, 26 32351706 Curated Info
10	Luo F, et al. (2019) Nonreceptor Tyrosine Kinase c-Abl- and Arg-Mediated IRF3 Phosphorylation Regulates Innate Immune Responses by Promoting Type I IFN Production. J Immunol 202, 2254-2265 30842273 Curated Info
11	Liu S, et al. (2017) Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses. Cell Host Microbe 21, 754-768.e5 28618271 Curated Info
12	Liu B, et al. (2017) The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination. Nat Immunol 18, 214-224 27992402 Curated Info
13	Meng F, et al. (2016) Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation. Genes Dev 30, 1086-100 27125670 Curated Info
14	Song S, et al. (2016) Fas-Associated Factor 1 Negatively Regulates the Antiviral Immune Response by Inhibiting Translocation of Interferon Regulatory Factor 3 to the Nucleus. Mol Cell Biol 36, 1136-51 26811330 Curated Info
15	Liu S, et al. (2015) Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 25636800 Curated Info
16	Zhang L, et al. (2014) Ubiquitin-Specific Protease 2b Negatively Regulates IFN-β Production and Antiviral Activity by Targeting TANK-Binding Kinase 1. J Immunol 193, 2230-7 25070846 Curated Info
17	Sgarbanti M, et al. (2014) IκB Kinase {varepsilon} Targets Interferon Regulatory Factor 1 in Activated T Lymphocytes. Mol Cell Biol 34, 1054-65 24396068 Curated Info
18	Das A, Dinh PX, Panda D, Pattnaik AK (2014) Interferon-inducible protein IFI35 negatively regulates RIG-I antiviral signaling and supports vesicular stomatitis virus replication. J Virol 88, 3103-13 24371060 Curated Info
19	Simicek M, et al. (2013) The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response. Nat Cell Biol 15, 1220-30 24056301 Curated Info
20	Gu L, Fullam A, Brennan R, Schröder M (2013) Human DEAD Box Helicase 3 Couples IκB Kinase {varepsilon} to Interferon Regulatory Factor 3 Activation. Mol Cell Biol 33, 2004-15 23478265 Curated Info
21	Yamashita M, et al. (2012) Epidermal growth factor receptor is essential for toll-like receptor 3 signaling. Sci Signal 5, ra50 22810896 Curated Info
22	Lei CQ, et al. (2010) Glycogen synthase kinase 3β regulates IRF3 transcription factor-mediated antiviral response via activation of the kinase TBK1. Immunity 33, 878-89 21145761 Curated Info
23	Bergstroem B, et al. (2010) Identification of a novel in vivo virus-targeted phosphorylation site in interferon regulatory factor-3 (IRF3). J Biol Chem 285, 24904-14 20511230 Curated Info
24	Yoboua F, et al. (2010) Respiratory syncytial virus-mediated NF-{kappa}B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK{beta}. J Virol 84, 7267-77 20410276 Curated Info
25	Fujii K, Nakamura S, Takahashi K, Inagaki F (2010) Systematic characterization by mass spectrometric analysis of phosphorylation sites in IRF-3 regulatory domain activated by IKK-i. J Proteomics 73, 1196-203 20170763 Curated Info
26	Nakhaei P, et al. (2009) The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation. PLoS Pathog 5, e1000650 19893624 Curated Info
27	Zhang B, et al. (2009) The TAK1-JNK cascade is required for IRF3 function in the innate immune response. Cell Res 19, 412-28 19153595 Curated Info
28	Chen W, et al. (2008) Contribution of Ser386 and Ser396 to activation of interferon regulatory factor 3. J Mol Biol 379, 251-60 18440553 Curated Info
29	McCoy CE, et al. (2008) Glucocorticoids inhibit IRF3 phosphorylation in response to Toll-like receptor-3 and -4 by targeting TBK1 activation. J Biol Chem 283, 14277-85 18356163 Curated Info
30	Clément JF, et al. (2008) Phosphorylation of IRF-3 on Ser 339 generates a hyperactive form of IRF-3 through regulation of dimerization and CBP association. J Virol 82, 3984-96 18272581 Curated Info
31	Chien Y, et al. (2006) RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127, 157-70 17018283 Curated Info
32	Saitoh T, et al. (2006) Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat Immunol 7, 598-605 16699525 Curated Info
33	Lin R, et al. (2006) Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. J Biol Chem 281, 2095-103 16306043 Curated Info
34	Paz S, et al. (2006) Induction of IRF-3 and IRF-7 phosphorylation following activation of the RIG-I pathway. Cell Mol Biol (Noisy-le-grand) 52, 17-28 16914100 Curated Info
35	Mori M, et al. (2004) Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. J Biol Chem 279, 9698-702 14703513 Curated Info
36	Servant MJ, et al. (2003) Identification of the minimal phosphoacceptor site required for in vivo activation of interferon regulatory factor 3 in response to virus and double-stranded RNA. J Biol Chem 278, 9441-7 12524442 Curated Info
37	Takauji R, et al. (2002) CpG-DNA-induced IFN-alpha production involves p38 MAPK-dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors. J Leukoc Biol 72, 1011-9 12429724 Curated Info
38	Lin R, Heylbroeck C, Pitha PM, Hiscott J (1998) Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol Cell Biol 18, 2986-96 9566918 Curated Info