Ser396
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Home > Phosphorylation Site Page: > Ser396  -  IRF3 (human)

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 

1

Lenoir JJ, Parisien JP, Horvath CM (2021) Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation. Cell Rep 37, 110175
34965427   Curated Info

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

8

Kesavan R, et al. (2020) Cyp2c44 regulates prostaglandin synthesis, lymphangiogenesis, and metastasis in a mouse model of breast cancer. Proc Natl Acad Sci U S A
32123095   Curated Info

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