泛素化调控抗病毒天然免疫的研究进展
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摘要
天然免疫是宿主防御病原微生物入侵的第一道防线,其活化主要通过天然免疫细胞上的模式识别受体(pattern recognition receptors, PRRs)识别病原微生物上相对保守的相关分子模式(pathogen-associated molecular patterns, PAMPs).病毒相关的核酸成分可以被机体Toll样受体(Toll-like receptors, TLRs)、维甲酸诱导基因Ⅰ受体(RIG-I-like receptors, RLRs)以及胞浆DNA受体(cytoplasmic DNA sensors)等识别,通过一系列复杂的细胞信号通路诱导Ⅰ型干扰素(typeⅠinterferon)及炎症因子的表达,从而激发机体抗病毒反应.泛素化修饰是细胞内广泛存在的蛋白质翻译后修饰方式,在宿主防御病原微生物感染的动态调控过程中发挥着重要的作用.已有大量文献报道,天然免疫抗病毒信号通路中的多个关键接头分子可发生泛素化修饰,进而调控机体抗病毒免疫应答反应.本文综述了泛素化修饰在抗病毒天然免疫中的作用及其调控机制.
Innate immunity is the first line of host defense against invading microbes. Activation of innate immunity primarily relies on the recognition of pathogen-associated molecular patterns(PAMPs) by pattern-recognition receptors(PRRs). Viral nucleic acids are recognized by the retinoic acid-inducible gene I(RIG-I)-like receptors(RLRs) and the Toll-like receptors(TLR) as well as the DNA sensor cyclic GMP-AMP(cGAMP) synthase(c GAS), leading to the production of proinflammatory cytokines and type I interferon and elimination of viral infection. Protein ubiquitination has emerged as a crucial mechanism that regulates signal transduction in diverse biological processes. A variety of key molecules in innate antiviral signaling transduction pathways can be ubiquitinated. The current review summarizes our current knowledge on the functions and regulatory mechanisms of protein ubiquitination in innate antiviral immunity with a focus on the E3 ligases.
Innate immunity is the first line of host defense against invading microbes. Activation of innate immunity primarily relies on the recognition of pathogen-associated molecular patterns(PAMPs) by pattern-recognition receptors(PRRs). Viral nucleic acids are recognized by the retinoic acid-inducible gene I(RIG-I)-like receptors(RLRs) and the Toll-like receptors(TLR) as well as the DNA sensor cyclic GMP-AMP(cGAMP) synthase(c GAS), leading to the production of proinflammatory cytokines and type I interferon and elimination of viral infection. Protein ubiquitination has emerged as a crucial mechanism that regulates signal transduction in diverse biological processes. A variety of key molecules in innate antiviral signaling transduction pathways can be ubiquitinated. The current review summarizes our current knowledge on the functions and regulatory mechanisms of protein ubiquitination in innate antiviral immunity with a focus on the E3 ligases.
引文
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4 Kawai T,Akira S.The role of pattern-recognition receptors in innate immunity:update on Toll-like receptors.Nat Immunol,2010,11:373-384
5 Akira S,Takeda K.Toll-like receptor signalling.Nat Rev Immunol,2004,4:499-511
6 O’Neill L A J,Bowie A G.The family of five:TIR-domain-containing adaptors in Toll-like receptor signalling.Nat Rev Immunol,2007,7:353-364
7 Oganesyan G,Saha S K,Guo B,et al.Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response.Nature,2006,439:208-211
8 H?cker H,Redecke V,Blagoev B,et al.Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.Nature,2006,439:204-207
9 Berke I C,Li Y,Modis Y.Structural basis of innate immune recognition of viral RNA.Cellul Microbiol,2013,15:386-394
10 Yoneyama M,Onomoto K,Jogi M,et al.Viral RNA detection by RIG-I-like receptors.Curr Opin Immunol,2015,32:48-53
11 Bruns A M,Leser G P,Lamb R A,et al.The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament assembly.Mol Cell,2014,55:771-781
12 Satoh T,Kato H,Kumagai Y,et al.LGP2 is a positive regulator of RIG-I-and MDA5-mediated antiviral responses.Proc Natl Acad Sci USA,2010,107:1512-1517
13 Kato H,Takeuchi O,Mikamo-Satoh E,et al.Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-Iand melanoma differentiation-associated gene 5.J Exp Med,2008,205:1601-1610
14 Wu B,Hur S.How RIG-Ⅰlike receptors activate MAVS.Curr Opin Virol,2015,12:91-98
15 Reikine S,Nguyen J B,Modis Y.Pattern recognition and signaling mechanisms of RIG-I and MDA5.Front Immunol,2014,5:342
16 Jacobs J L,Coyne C B.Mechanisms of MAVS regulation at the mitochondrial membrane.J Mol Biol,2013,425:5009-5019
17 Boga J,de Ona M,Melon S,et al.MAVS:a new weapon in the fight against viral infections.Recent Patent Endocr Metab Immune Drug Discov,2013,7:115-119
18 Zhang X,Wu J,Du F,et al.The cytosolic DNA sensor c GAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop.Cell Rep,2014,6:421-430
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31 Yang Y,Liao B,Wang S,et al.E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation.Proc Natl Acad Sci USA,2013,110:5115-5120
32 Xue Q,Zhou Z,Lei X,et al.TRIM38 negatively regulates TLR3-mediated IFN-βsignaling by targeting TRIF for degradation.PLoS ONE,2012,7:e46825
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36 Fiil B K,Gyrd-Hansen M.Met1-linked ubiquitination in immune signalling.FEBS J,2014,281:4337-4350
37 Zotti T,Uva A,Ferravante A,et al.TRAF7 protein promotes Lys-29-linked polyubiquitination of IκB kinase(IKKγ)/NF-κB essential modulator(NEMO)and p65/RelA protein and represses NF-κB activation.J Biol Chem,2011,286:22924-22933
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39 Nakhaei P,Mesplede T,Solis M,et al.The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation.PLoS Pathog,2009,5:e1000650
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45 Lei C Q,Zhang Y,Xia T,et al.FoxO1 negatively regulates cellular antiviral response by promoting degradation of IRF3.J Biol Chem,2013,288:12596-12604
46 Higgs R,Gabhann J N,Larbi N B,et al.The E3 ubiquitin ligase Ro52 negatively regulates IFN-production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3.J Immunol,2008,181:1780-1786
47 Yu Y,Hayward G S.The ubiquitin E3 ligase RAUL negatively regulates type I interferon through ubiquitination of the transcription factors IRF7and IRF3.Immunity,2010,33:863-877
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2 Sadler A J,Williams B R G.Interferon-inducible antiviral effectors.Nat Rev Immunol,2008,8:559-568
3 Barrat F J,Elkon K B,Fitzgerald K A.Importance of nucleic acid recognition in inflammation and autoimmunity.Annu Rev Med,2016,67:323-336
4 Kawai T,Akira S.The role of pattern-recognition receptors in innate immunity:update on Toll-like receptors.Nat Immunol,2010,11:373-384
5 Akira S,Takeda K.Toll-like receptor signalling.Nat Rev Immunol,2004,4:499-511
6 O’Neill L A J,Bowie A G.The family of five:TIR-domain-containing adaptors in Toll-like receptor signalling.Nat Rev Immunol,2007,7:353-364
7 Oganesyan G,Saha S K,Guo B,et al.Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response.Nature,2006,439:208-211
8 H?cker H,Redecke V,Blagoev B,et al.Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.Nature,2006,439:204-207
9 Berke I C,Li Y,Modis Y.Structural basis of innate immune recognition of viral RNA.Cellul Microbiol,2013,15:386-394
10 Yoneyama M,Onomoto K,Jogi M,et al.Viral RNA detection by RIG-I-like receptors.Curr Opin Immunol,2015,32:48-53
11 Bruns A M,Leser G P,Lamb R A,et al.The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament assembly.Mol Cell,2014,55:771-781
12 Satoh T,Kato H,Kumagai Y,et al.LGP2 is a positive regulator of RIG-I-and MDA5-mediated antiviral responses.Proc Natl Acad Sci USA,2010,107:1512-1517
13 Kato H,Takeuchi O,Mikamo-Satoh E,et al.Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-Iand melanoma differentiation-associated gene 5.J Exp Med,2008,205:1601-1610
14 Wu B,Hur S.How RIG-Ⅰlike receptors activate MAVS.Curr Opin Virol,2015,12:91-98
15 Reikine S,Nguyen J B,Modis Y.Pattern recognition and signaling mechanisms of RIG-I and MDA5.Front Immunol,2014,5:342
16 Jacobs J L,Coyne C B.Mechanisms of MAVS regulation at the mitochondrial membrane.J Mol Biol,2013,425:5009-5019
17 Boga J,de Ona M,Melon S,et al.MAVS:a new weapon in the fight against viral infections.Recent Patent Endocr Metab Immune Drug Discov,2013,7:115-119
18 Zhang X,Wu J,Du F,et al.The cytosolic DNA sensor c GAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop.Cell Rep,2014,6:421-430
19 Cai X,Chiu Y H,Chen Z J.The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling.Mol Cell,2014,54:289-296
20 Burrows J F,Johnston J A.Regulation of cellular responses by deubiquitinating enzymes:an update.Front Biosci,2012,17:1184-1200
21 Berndsen C E,Wolberger C.New insights into ubiquitin E3 ligase mechanism.Nat Struct Mol Biol,2014,21:301-307
22 Mattiroli F,Sixma T K.Lysine-targeting specificity in ubiquitin and ubiquitin-like modification pathways.Nat Struct Mol Biol,2014,21:308-31623 Deshaies R J,Joazeiro C A P.RING domain E3 ubiquitin ligases.Annu Rev Biochem,2009,78:399-434
24 Komander D,Rape M.The ubiquitin code.Annu Rev Biochem,2012,81:203-229
25 Kirisako T,Kamei K,Murata S,et al.A ubiquitin ligase complex assembles linear polyubiquitin chains.EMBO J,2006,25:4877-4887
26 Liu J,Qian C,Cao X.Post-translational modification control of innate immunity.Immunity,2016,45:15-30
27 Heaton S M,Borg N A,Dixit V M.Ubiquitin in the activation and attenuation of innate antiviral immunity.J Exp Med,2016,213:1-13
28 Chuang T H,Ulevitch R J.Triad3A,an E3 ubiquitin-protein ligase regulating Toll-like receptors.Nat Immunol,2004,5:495-502
29 Lee Y S,Park J S,Kim J H,et al.Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4signalling.Nat Commun,2011,2:460
30 Wang C,Chen T,Zhang J,et al.The E3 ubiquitin ligase Nrdp1“preferentially”promotes TLR-mediated production of type I interferon.Nat Immunol,2009,10:744-752
31 Yang Y,Liao B,Wang S,et al.E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation.Proc Natl Acad Sci USA,2013,110:5115-5120
32 Xue Q,Zhou Z,Lei X,et al.TRIM38 negatively regulates TLR3-mediated IFN-βsignaling by targeting TRIF for degradation.PLoS ONE,2012,7:e46825
33 Liu S,Chen Z J.Expanding role of ubiquitination in NF-κB signaling.Cell Res,2011,21:6-21
34 H?cker H,Tseng P H,Karin M.Expanding TRAF function:TRAF3 as a tri-faced immune regulator.Nat Rev Immunol,2011,11:457-468
35 Liu J,Han C,Xie B,et al.Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO.Nat Immunol,2014,15:612-622
36 Fiil B K,Gyrd-Hansen M.Met1-linked ubiquitination in immune signalling.FEBS J,2014,281:4337-4350
37 Zotti T,Uva A,Ferravante A,et al.TRAF7 protein promotes Lys-29-linked polyubiquitination of IκB kinase(IKKγ)/NF-κB essential modulator(NEMO)and p65/RelA protein and represses NF-κB activation.J Biol Chem,2011,286:22924-22933
38 Song G,Liu B,Li Z,et al.E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1.Nat Immunol,2016,17:1342-1351
39 Nakhaei P,Mesplede T,Solis M,et al.The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation.PLoS Pathog,2009,5:e1000650
40 Cui J,Li Y,Zhu L,et al.NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4.Nat Immunol,2012,13:387-395
41 Zhang M,Wang L,Zhao X,et al.TRAF-interacting protein(TRIP)negatively regulates IFN-βproduction and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1.J Exp Med,2012,209:1703-1711
42 Wang P,Zhao W,Zhao K,et al.TRIM26 negatively regulates interferon-βproduction and antiviral response through polyubiquitination and degradation of nuclear IRF3.PLoS Pathog,2015,11:e1004726
43 Saitoh T,Tun-Kyi A,Ryo A,et al.Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1.Nat Immunol,2006,7:598-605
44 Zhang M,Tian Y,Wang R P,et al.Negative feedback regulation of cellular antiviral signaling by RBCK1-mediated degradation of IRF3.Cell Res,2008,18:1096-1104
45 Lei C Q,Zhang Y,Xia T,et al.FoxO1 negatively regulates cellular antiviral response by promoting degradation of IRF3.J Biol Chem,2013,288:12596-12604
46 Higgs R,Gabhann J N,Larbi N B,et al.The E3 ubiquitin ligase Ro52 negatively regulates IFN-production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3.J Immunol,2008,181:1780-1786
47 Yu Y,Hayward G S.The ubiquitin E3 ligase RAUL negatively regulates type I interferon through ubiquitination of the transcription factors IRF7and IRF3.Immunity,2010,33:863-877
48 Oshiumi H,Matsumoto M,Hatakeyama S,et al.Riplet/RNF135,a ring finger protein,ubiquitinates RIG-Ⅰto promote interferon-βinduction during the early phase of viral infection.J Biol Chem,2009,284:807-817
49 Yan J,Li Q,Mao A P,et al.TRIM4 modulates type I interferon induction and cellular antiviral response by targeting RIG-I for K63-linked ubiquitination.J Mol Cell Biol,2014,6:154-163
50 Kuniyoshi K,Takeuchi O,Pandey S,et al.Pivotal role of RNA-binding E3 ubiquitin ligase MEX3C in RIG-I-mediated antiviral innate immunity.Proc Natl Acad Sci USA,2014,111:5646-5651
51 Zeng W,Sun L,Jiang X,et al.Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity.Cell,2010,141:315-330
52 Gack M U,Shin Y C,Joo C H,et al.TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity.Nature,2007,446:916-920
53 Inn K S,Gack M U,Tokunaga F,et al.Linear ubiquitin assembly complex negatively regulates RIG-I-and TRIM25-mediated type I interferon induction.Mol Cell,2011,41:354-365
54 Paz S,Vilasco M,Werden S J,et al.A functional C-terminal TRAF3-binding site in MAVS participates in positive and negative regulation of the IFN antiviral response.Cell Res,2011,21:895-910
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