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 ( 27 , 29 ) , immunoprecipitation ( 2 , 4 , 18 ) , mass spectrometry ( 2 , 14 , 16 ) , mass spectrometry (in vitro) ( 14 ) , mutation of modification site ( 2 , 3 , 4 , 7 , 14 , 18 , 21 , 23 , 27 , 29 ) , phospho-antibody ( 1 , 4 , 5 , 6 , 9 , 12 , 13 , 15 , 17 , 20 , 22 , 23 , 24 , 27 ) , western blotting ( 1 , 2 , 4 , 5 , 6 , 9 , 12 , 13 , 15 , 17 , 18 , 20 , 22 , 23 , 24 )
Disease tissue studied:	brain cancer ( 20 ) , glioblastoma ( 20 ) , glioblastoma multiforme ( 20 ) , glioma ( 20 ) , breast cancer ( 12 ) , lung cancer ( 15 ) , fibrosarcoma of soft tissue ( 1 )
Relevant cell line - cell type - tissue:	293 (epithelial) ( 4 , 7 , 9 , 13 , 14 , 17 , 23 , 24 , 27 , 29 ) , A549 (pulmonary) ( 15 ) , COS (fibroblast) ( 29 ) , E.coli (bacterial) [IKKE (human), transfection] ( 16 ) , HEC-1B (endometrial) ( 27 ) , HEK293T (epithelial) ( 2 , 3 , 18 ) , HeLa (cervical) ( 5 , 21 ) , HT1080 (fibroblast) ( 1 ) , MDA-MB-453 (breast cell) ( 12 ) , MEF (fibroblast) ( 6 , 22 ) , mononuclear ( 20 ) , U-937 (myeloid) ( 27 ) , U373 MG (glial) [CD14 (human), transfection] ( 20 ) , U373 MG (glial) ( 27 )

Upstream Regulation
Regulatory protein:	DDX3 (human) ( 11 ) , DDX58 (human) ( 17 , 24 ) , EGFR (human) ( 12 ) , GSK3B (human) ( 13 ) , IFI35 (human) ( 9 ) , IKKE (human) ( 15 ) , MAVS (human) ( 17 ) , MST1 (human) ( 4 ) , ROBO3 (human) ( 5 ) , TBK1 (human) ( 15 , 17 , 24 ) , TICAM1 (human) ( 24 ) , TNFAIP3 (human) ( 24 ) , TRIAD3 (human) ( 17 )
Putative in vivo kinases:	IKKB (human) ( 18 ) , IKKE (human) ( 16 ) , TBK1 (human) ( 18 )
Kinases, in vitro:	IKKE (human) ( 21 , 25 ) , TBK1 (human) ( 14 , 21 , 25 )
Treatments:	CpG ( 28 ) , dexamethasone ( 20 ) , double-stranded_RNA ( 27 ) , dsDNA ( 1 ) , LPS ( 20 , 23 ) , poly(I-C) ( 20 , 22 , 23 ) , RO-3306 ( 1 ) , virus infection ( 13 , 14 , 15 , 21 , 22 , 27 , 29 )

Downstream Regulation
Effects of modification on IRF3:	activity, induced ( 21 , 27 ) , activity, inhibited ( 9 ) , intracellular localization ( 21 , 29 ) , molecular association, regulation ( 14 , 19 , 21 , 26 , 29 ) , protein conformation ( 6 ) , protein degradation ( 21 )
Effects of modification on biological processes:	transcription, altered ( 18 , 27 ) , transcription, induced ( 3 , 7 )
Induce interaction with:	CBP (human) ( 14 , 19 , 21 , 29 ) , IRF3 (human) ( 19 , 21 , 26 )

References
1	Zhong L, et al. (2020) Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis. Cell Discov 6, 26 32351706 Curated Info
2	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
3	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
4	Meng F, et al. (2016) Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation. Genes Dev 30, 1086-100 27125670 Curated Info
5	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
6	Liu S, et al. (2015) Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 25636800 Curated Info
7	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
8	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
9	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
10	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
11	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
12	Yamashita M, et al. (2012) Epidermal growth factor receptor is essential for toll-like receptor 3 signaling. Sci Signal 5, ra50 22810896 Curated Info
13	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
14	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
15	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
16	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
17	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
18	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
19	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
20	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
21	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
22	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
23	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
24	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
25	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
26	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
27	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
28	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
29	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