Journal List > Immune Netw > v.18(1) > 1148258

Li and Zhong: Regulation of Cellular Antiviral Signaling by Modifications of Ubiquitin and Ubiquitin-like Molecules

Abstract

The initiation of cellular antiviral signaling depends on host pattern-recognition receptors (PRRs)-mediated recognition of viral nucleic acids that are known as classical pathogen-associated molecular patterns (PAMPs). PRRs recruit adaptor proteins and kinases to activate transcription factors and epigenetic modifiers to regulate transcription of hundreds of genes, the products of which collaborate to elicit antiviral responses. In addition, PRRs-triggered signaling induces activation of various inflammasomes which leads to the release of IL-1β and inflammation. Recent studies have demonstrated that PRRs-triggered signaling is critically regulated by ubiquitin and ubiquitin-like molecules. In this review, we first summarize an updated understanding of cellular antiviral signaling and virus-induced activation of inflammasome and then focus on the regulation of key components by ubiquitin and ubiquitin-like molecules.

References

1. Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989; 54:1–13.
crossref
2. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010; 140:805–820.
crossref
3. Wu J, Chen ZJ. Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol. 2014; 32:461–488.
crossref
4. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 2005; 6:981–988.
crossref
5. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005; 437:1167–1172.
crossref
6. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005; 19:727–740.
7. Seth RB, Sun L, Ea CK, Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005; 122:669–682.
8. Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013; 339:786–791.
crossref
9. Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science. 2013; 341:1390–1394.
crossref
10. Chiu YH, Macmillan JB, Chen ZJ. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell. 2009; 138:576–591.
crossref
11. Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol. 2009; 10:1065–1072.
crossref
12. Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, Lei C, He X, Zhang L, Tien P, et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity. 2008; 29:538–550.
crossref
13. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008; 455:674–678.
crossref
14. Man SM, Karki R, Kanneganti TD. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 2017; 277:61–75.
crossref
15. Yang J, Liu Z, Xiao TS. Post-translational regulation of inflammasomes. Cell Mol Immunol. 2017; 14:65–79.
crossref
16. Komander D, Rape M. The ubiquitin code. Annu Rev Biochem. 2012; 81:203–229.
crossref
17. Mevissen TE, Komander D. Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem. 2017; 86:159–192.
crossref
18. Enchev RI, Schulman BA, Peter M. Protein neddylation: beyond cullin-RING ligases. Nat Rev Mol Cell Biol. 2015; 16:30–44.
crossref
19. dos Santos PF, Mansur DS. Beyond ISGlylation: functions of free intracellular and extracellular ISG15. J Interferon Cytokine Res. 2017; 37:246–253.
crossref
20. Dhingra N, Zhao X. A guide for targeted SUMO removal. Genes Dev. 2017; 31:719–720.
crossref
21. Xia P, Wang S, Xiong Z, Ye B, Huang LY, Han ZG, Fan Z. IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation. Nat Commun. 2015; 6:8132.
crossref
22. Yang P, Ma J, Zhang B, Duan H, He Z, Zeng J, Zeng X, Li D, Wang Q, Xiao Y, et al. CpG site-specific hypermethylation of p16INK4α in peripheral blood lymphocytes of PAH-exposed workers. Cancer Epidemiol Biomarkers Prev. 2012; 21:182–190.
crossref
23. Skaug B, Chen ZJ. Emerging role of ISG15 in antiviral immunity. Cell. 2010; 143:187–190.
crossref
24. Liu B, Zhang M, Chu H, Zhang H, Wu H, Song G, Wang P, Zhao K, Hou J, Wang X, et al. The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination. Nat Immunol. 2017; 18:214–224.
crossref
25. Wang Q, Liu X, Cui Y, Tang Y, Chen W, Li S, Yu H, Pan Y, Wang C. The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. Immunity. 2014; 41:919–933.
26. Zhang J, Hu MM, Wang YY, Shu HB. TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination. J Biol Chem. 2012; 287:28646–28655.
crossref
27. Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, Kawai T, Akira S. The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA. Immunity. 2010; 33:765–776.
crossref
28. Michallet MC, Meylan E, Ermolaeva MA, Vazquez J, Rebsamen M, Curran J, Poeck H, Bscheider M, Hartmann G, König M, et al. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity. 2008; 28:651–661.
crossref
29. Liu S, Chen J, Cai X, Wu J, Chen X, Wu YT, Sun L, Chen ZJ. MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. ELife. 2013; 2:e00785.
crossref
30. Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, Du F, Ren J, Wu YT, Grishin NV, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015; 347:aaa2630.
crossref
31. Shinohara ML, Lu L, Bu J, Werneck MB, Kobayashi KS, Glimcher LH, Cantor H. Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat Immunol. 2006; 7:498–506.
32. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005; 434:772–777.
crossref
33. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, Taya C, Taniguchi T. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature. 2005; 434:1035–1040.
crossref
34. Lu B, Ren Y, Sun X, Han C, Wang H, Chen Y, Peng Q, Cheng Y, Cheng X, Zhu Q, et al. Induction of INKIT by viral infection negatively regulates antiviral responses through inhibiting phosphorylation of p65 and IRF3. Cell Host Microbe. 2017; 22:86–98. e4.
crossref
35. Jin J, Hu H, Li HS, Yu J, Xiao Y, Brittain GC, Zou Q, Cheng X, Mallette FA, Watowich SS, et al. Noncanonical NF-κ B pathway controls the production of type I interferons in antiviral innate immunity. Immunity. 2014; 40:342–354.
crossref
36. Mathur A, Hayward JA, Man SM. Molecular mechanisms of inflammasome signaling. J Leukoc Biol.DOI: doi: 10.1189/jlb.3MR0617–250R.
crossref
37. Schroder K, Tschopp J. The inflammasomes. Cell. 2010; 140:821–832.
crossref
38. Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, Vanaja SK, Monks BG, Ganesan S, Latz E, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol. 2010; 11:395–402.
crossref
39. Singh VV, Kerur N, Bottero V, Dutta S, Chakraborty S, Ansari MA, Paudel N, Chikoti L, Chandran B. Kaposi's sarcoma-associated herpesvirus latency in endothelial and B cells activates gamma interferon-inducible protein 16-mediated inflammasomes. J Virol. 2013; 87:4417–4431.
crossref
40. Johnson KE, Chikoti L, Chandran B. Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol. 2013; 87:5005–5018.
crossref
41. Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, Hannesschläger N, Schlee M, Rothenfusser S, Barchet W, et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol. 2010; 11:63–69.
42. Chattergoon MA, Latanich R, Quinn J, Winter ME, Buckheit RW 3rd, Blankson JN, Pardoll D, Cox AL. HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Toll-like receptors without induction of type 1 interferon. PLoS Pathog. 2014; 10:e1004082.
crossref
43. Ogura Y, Sutterwala FS, Flavell RA. The inflammasome: first line of the immune response to cell stress. Cell. 2006; 126:659–662.
crossref
44. Oda T, Akaike T, Hamamoto T, Suzuki F, Hirano T, Maeda H. Oxygen radicals in influenza-induced pathogenesis and treatment with pyran polymer-conjugated SOD. Science. 1989; 244:974–976.
crossref
45. Ichinohe T, Pang IK, Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol. 2010; 11:404–410.
crossref
46. Rahman MM, McFadden G. Myxoma virus lacking the pyrin-like protein M013 is sensed in human myeloid cells by both NLRP3 and multiple Toll-like receptors, which independently activate the inflammasome and NF-κ B innate response pathways. J Virol. 2011; 85:12505–12517.
crossref
47. Martin BN, Wang C, Willette-Brown J, Herjan T, Gulen MF, Zhou H, Bulek K, Franchi L, Sato T, Alnemri ES, et al. IKKα negatively regulates ASC-dependent inflammasome activation. Nat Commun. 2014; 5:4977.
crossref
48. Wang Y, Ning X, Gao P, Wu S, Sha M, Lv M, Zhou X, Gao J, Fang R, Meng G, et al. Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection. Immunity. 2017; 46:393–404.
crossref
49. Lin D, Zhong B. Regulation of cellular innate antiviral signaling by ubiquitin modification. Acta Biochim Biophys Sin (Shanghai). 2015; 47:149–155.
crossref
50. Liu W, Li J, Zheng W, Shang Y, Zhao Z, Wang S, Bi Y, Zhang S, Xu C, Duan Z, et al. Cyclophilin A-regulated ubiquitination is critical for RIG-I-mediated antiviral immune responses. ELife. 2017; 6:e24425.
crossref
51. Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, Takeuchi O, Akira S, Chen Z, Inoue S, et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature. 2007; 446:916–920.
crossref
52. Shi Y, Yuan B, Zhu W, Zhang R, Li L, Hao X, Chen S, Hou F. Ube2D3 and Ube2N are essential for RIG-I-mediated MAVS aggregation in antiviral innate immunity. Nat Commun. 2017; 8:15138.
crossref
53. Sun X, Xian H, Tian S, Sun T, Qin Y, Zhang S, Cui J. A hierarchical mechanism of RIG-I ubiquitination provides sensitivity, robustness and synergy in antiviral immune responses. Sci Rep. 2016; 6:29263.
crossref
54. Xian H, Xie W, Yang S, Liu Q, Xia X, Jin S, Sun T, Cui J. Stratified ubiquitination of RIG-I creates robust immune response and induces selective gene expression. Sci Adv. 2017; 3:e1701764.
crossref
55. Hao Q, Jiao S, Shi Z, Li C, Meng X, Zhang Z, Wang Y, Song X, Wang W, Zhang R, et al. A non-canonical role of the p97 complex in RIG-I antiviral signaling. EMBO J. 2015; 34:2903–2920.
56. Wang W, Jiang M, Liu S, Zhang S, Liu W, Ma Y, Zhang L, Zhang J, Cao X. RNF122 suppresses antiviral type I interferon production by targeting RIG-I CARDs to mediate RIG-I degradation. Proc Natl Acad Sci U S A. 2016; 113:9581–9586.
crossref
57. Arimoto K, Takahashi H, Hishiki T, Konishi H, Fujita T, Shimotohno K. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci U S A. 2007; 104:7500–7505.
crossref
58. Chen W, Han C, Xie B, Hu X, Yu Q, Shi L, Wang Q, Li D, Wang J, Zheng P, et al. Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell. 2013; 152:467–478.
crossref
59. Zhao C, Jia M, Song H, Yu Z, Wang W, Li Q, Zhang L, Zhao W, Cao X. The E3 ubiquitin ligase TRIM40 attenuates antiviral immune responses by targeting MDA5 and RIG-I. Cell Rep. 2017; 21:1613–1623.
60. Zhang H, Wang D, Zhong H, Luo R, Shang M, Liu D, Chen H, Fang L, Xiao S. Ubiquitin-specific protease 15 negatively regulates virus-induced type I interferon signaling via catalytically-dependent and -independent mechanisms. Sci Rep. 2015; 5:11220.
crossref
61. Pauli EK, Chan YK, Davis ME, Gableske S, Wang MK, Feister KF, Gack MU. The ubiquitin-specific protease USP15 promotes RIG-I-mediated antiviral signaling by deubiquitylating TRIM25. Sci Signal. 2014; 7:ra3.
crossref
62. Zhang M, Wu X, Lee AJ, Jin W, Chang M, Wright A, Imaizumi T, Sun SC. Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem. 2008; 283:18621–18626.
63. Chen R, Zhang L, Zhong B, Tan B, Liu Y, Shu HB. The ubiquitin-specific protease 17 is involved in virus-triggered type I IFN signaling. Cell Res. 2010; 20:802–811.
crossref
64. Wang L, Zhao W, Zhang M, Wang P, Zhao K, Zhao X, Yang S, Gao C. USP4 positively regulates RIG-I-mediated antiviral response through deubiquitination and stabilization of RIG-I. J Virol. 2013; 87:4507–4515.
crossref
65. Cui J, Song Y, Li Y, Zhu Q, Tan P, Qin Y, Wang HY, Wang RF. USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cell Res. 2014; 24:400–416.
crossref
66. Fan Y, Mao R, Yu Y, Liu S, Shi Z, Cheng J, Zhang H, An L, Zhao Y, Xu X, et al. USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase. J Exp Med. 2014; 211:313–328.
crossref
67. Lang X, Tang T, Jin T, Ding C, Zhou R, Jiang W. TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity. J Exp Med. 2017; 214:459–473.
crossref
68. Wang Q, Huang L, Hong Z, Lv Z, Mao Z, Tang Y, Kong X, Li S, Cui Y, Liu H, et al. The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response. PLoS Pathog. 2017; 13:e1006264.
crossref
69. Chen M, Meng Q, Qin Y, Liang P, Tan P, He L, Zhou Y, Chen Y, Huang J, Wang RF, et al. TRIM14 inhibits cGAS degradation mediated by selective autophagy receptor p62 to promote innate immune responses. Mol Cell. 2016; 64:105–119.
crossref
70. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012; 13:255–263.
crossref
71. Han S, Lear TB, Jerome JA, Rajbhandari S, Snavely CA, Gulick DL, Gibson KF, Zou C, Chen BB, Mallampalli RK. Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SCFFBXL2 E3 ligase. J Biol Chem. 2015; 290:18124–18133.
crossref
72. Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, Zhou R. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell. 2015; 160:62–73.
crossref
73. Xue Q, Zhou Z, Lei X, Liu X, He B, Wang J, Hung T. TRIM38 negatively regulates TLR3-mediated IFN-β signaling by targeting TRIF for degradation. PLoS One. 2012; 7:e46825.
crossref
74. Hu MM, Xie XQ, Yang Q, Liao CY, Ye W, Lin H, Shu HB. TRIM38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms. J Immunol. 2015; 195:4415–4425.
crossref
75. Yang Y, Liao B, Wang S, Yan B, Jin Y, Shu HB, Wang YY. E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation. Proc Natl Acad Sci U S A. 2013; 110:5115–5120.
crossref
76. Yang Q, Liu TT, Lin H, Zhang M, Wei J, Luo WW, Hu YH, Zhong B, Hu MM, Shu HB. TRIM32-TAX1BP1-dependent selective autophagic degradation of TRIF negatively regulates TLR3/4-mediated innate immune responses. PLoS Pathog. 2017; 13:e1006600.
crossref
77. Lee BC, Miyata M, Lim JH, Li JD. Deubiquitinase CYLD acts as a negative regulator for bacterium NTHi-induced inflammation by suppressing K63-linked ubiquitination of MyD88. Proc Natl Acad Sci U S A. 2016; 113:E165–E171.
crossref
78. Naiki Y, Michelsen KS, Zhang W, Chen S, Doherty TM, Arditi M. Transforming growth factor-beta differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling. J Biol Chem. 2005; 280:5491–5495.
79. Strickson S, Campbell DG, Emmerich CH, Knebel A, Plater L, Ritorto MS, Shpiro N, Cohen P. The anti-inflammatory drug BAY 11–7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system. Biochem J. 2013; 451:427–437.
crossref
80. Ji S, Sun M, Zheng X, Li L, Sun L, Chen D, Sun Q. Cell-surface localization of Pellino antagonizes Toll-mediated innate immune signalling by controlling MyD88 turnover in Drosophila. Nat Commun. 2014; 5:3458.
crossref
81. Wang C, Chen T, Zhang J, Yang M, Li N, Xu X, Cao X. The E3 ubiquitin ligase Nrdp1 ‘preferentially'promotes TLR-mediated production of type I interferon. Nat Immunol. 2009; 10:744–752.
crossref
82. Jin S, Tian S, Luo M, Xie W, Liu T, Duan T, Wu Y, Cui J. Tetherin suppresses type I interferon signaling by targeting MAVS for NDP52-mediated selective autophagic degradation in human cells. Mol Cell. 2017; 68:308–322. e4.
crossref
83. Xing J, Zhang A, Zhang H, Wang J, Li XC, Zeng MS, Zhang Z. TRIM29 promotes DNA virus infections by inhibiting innate immune response. Nat Commun. 2017; 8:945.
crossref
84. Ni G, Konno H, Barber GN. Ubiquitination of STING at lysine 224 controls IRF3 activation. Sci Immunol. 2017; 2:eaah7119.
crossref
85. Wang Y, Lian Q, Yang B, Yan S, Zhou H, He L, Lin G, Lian Z, Jiang Z, Sun B. TRIM30α is a negative-feedback regulator of the intracellular DNA and DNA virus-triggered response by targeting STING. PLoS Pathog. 2015; 11:e1005012.
crossref
86. Zhang M, Zhang MX, Zhang Q, Zhu GF, Yuan L, Zhang DE, Zhu Q, Yao J, Shu HB, Zhong B. USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA. Cell Res. 2016; 26:1302–1319.
crossref
87. Sun H, Zhang Q, Jing YY, Zhang M, Wang HY, Cai Z, Liuyu T, Zhang ZD, Xiong TC, Wu Y, et al. USP13 negatively regulates antiviral responses by deubiquitinating STING. Nat Commun. 2017; 8:15534.
crossref
88. Chen Y, Wang L, Jin J, Luan Y, Chen C, Li Y, Chu H, Wang X, Liao G, Yu Y, et al. p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation. J Exp Med. 2017; 214:991–1010.
crossref
89. Mao AP, Li S, Zhong B, Li Y, Yan J, Li Q, Teng C, Shu HB. Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral response. J Biol Chem. 2010; 285:9470–9476.
90. Wang C, Huang Y, Sheng J, Huang H, Zhou J. Estrogen receptor alpha inhibits RLR-mediated immune response via ubiquitinating TRAF3. Cell Signal. 2015; 27:1977–1983.
crossref
91. Peng Y, Xu R, Zheng X. HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1. PLoS Pathog. 2014; 10:e1004041.
crossref
92. Li S, Zheng H, Mao AP, Zhong B, Li Y, Liu Y, Gao Y, Ran Y, Tien P, Shu HB. Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6. J Biol Chem. 2010; 285:4291–4297.
crossref
93. Lin D, Zhang M, Zhang MX, Ren Y, Jin J, Zhao Q, Pan Z, Wu M, Shu HB, Dong C, et al. Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6. Proc Natl Acad Sci U S A. 2015; 112:11324–11329.
crossref
94. Panda S, Nilsson JA, Gekara NO. Deubiquitinase MYSM1 regulates innate immunity through inactivation of TRAF3 and TRAF6 complexes. Immunity. 2015; 43:647–659.
crossref
95. Guan K, Wei C, Zheng Z, Song T, Wu F, Zhang Y, Cao Y, Ma S, Chen W, Xu Q, et al. MAVS promotes inflammasome activation by targeting ASC for K63-linked ubiquitination via the E3 ligase TRAF3. J Immunol. 2015; 194:4880–4890.
crossref
96. An T, Li S, Pan W, Tien P, Zhong B, Shu HB, Wu S. DYRK2 negatively regulates type I interferon induction by promoting TBK1 degradation via Ser527 phosphorylation. PLoS Pathog. 2015; 11:e1005179.
crossref
97. Wildling L, Unterauer B, Zhu R, Rupprecht A, Haselgrübler T, Rankl C, Ebner A, Vater D, Pollheimer P, Pohl EE, et al. Linking of sensor molecules with amino groups to amino-functionalized AFM tips. Bioconjug Chem. 2011; 22:1239–1248.
crossref
98. Song G, Liu B, Li Z, Wu H, Wang P, Zhao K, Jiang G, Zhang L, Gao C. E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1. Nat Immunol. 2016; 17:1342–1351.
crossref
99. Zhao X, Zhu H, Yu J, Li H, Ge J, Chen W. c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-β production and cellular antiviral response. Cell Signal. 2016; 28:1683–1693.
crossref
100. Chattopadhyay S, Kuzmanovic T, Zhang Y, Wetzel JL, Sen GC. Ubiquitination of the transcription factor IRF-3 activates RIPA, the apoptotic pathway that protects mice from viral pathogenesis. Immunity. 2016; 44:1151–1161.
crossref
101. Ning S, Campos AD, Darnay BG, Bentz GL, Pagano JS. TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1. Mol Cell Biol. 2008; 28:6536–6546.
crossref
102. Decque A, Joffre O, Magalhaes JG, Cossec JC, Blecher-Gonen R, Lapaquette P, Silvin A, Manel N, Joubert PE, Seeler JS, et al. Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing. Nat Immunol. 2016; 17:140–149.
crossref
103. Mi Z, Fu J, Xiong Y, Tang H. SUMOylation of RIG-I positively regulates the type I interferon signaling. Protein Cell. 2010; 1:275–283.
crossref
104. Fu J, Xiong Y, Xu Y, Cheng G, Tang H. MDA5 is SUMOylated by PIAS2β in the upregulation of type I interferon signaling. Mol Immunol. 2011; 48:415–422.
crossref
105. Doiron K, Goyon V, Coyaud E, Rajapakse S, Raught B, McBride HM. The dynamic interacting landscape of MAPL reveals essential functions for SUMOylation in innate immunity. Sci Rep. 2017; 7:107.
crossref
106. Hu MM, Liao CY, Yang Q, Xie XQ, Shu HB. Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5. J Exp Med. 2017; 214:973–989.
crossref
107. Hu MM, Yang Q, Xie XQ, Liao CY, Lin H, Liu TT, Yin L, Shu HB. Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor STING to regulate the kinetics of response to DNA virus. Immunity. 2016; 45:555–569.
crossref
108. Cui Y, Yu H, Zheng X, Peng R, Wang Q, Zhou Y, Wang R, Wang J, Qu B, Shen N, et al. SENP7 potentiates cGAS activation by relieving SUMO-mediated inhibition of cytosolic DNA sensing. PLoS Pathog. 2017; 13:e1006156.
crossref
109. Sankineni S, Cho Y, Hosseinian N, Kolliputi N. Does pIgR down-regulation in COPD cause reprogramming of bronchial epithelium? Lung. 2015; 193:1–2.
crossref
110. Kubota T, Matsuoka M, Chang TH, Tailor P, Sasaki T, Tashiro M, Kato A, Ozato K. Virus infection triggers SUMOylation of IRF3 and IRF7, leading to the negative regulation of type I interferon gene expression. J Biol Chem. 2008; 283:25660–25670.
crossref
111. Liang Q, Deng H, Li X, Wu X, Tang Q, Chang TH, Peng H, Rauscher FJ 3rd, Ozato K, Zhu F. Tripartite motif-containing protein 28 is a small ubiquitin-related modifier E3 ligase and negative regulator of IFN regulatory factor 7. J Immunol. 2011; 187:4754–4763.
crossref
112. Li R, Pan Y, Shi DD, Zhang Y, Zhang J. PIAS1 negatively modulates virus triggered type I IFN signaling by blocking the DNA binding activity of IRF3. Antiviral Res. 2013; 100:546–554.
crossref
113. Lumpkin RJ, Gu H, Zhu Y, Leonard M, Ahmad AS, Clauser KR, Meyer JG, Bennett EJ, Komives EA. Site-specific identification and quantitation of endogenous SUMO modifications under native conditions. Nat Commun. 2017; 8:1171.
crossref
114. Lamoliatte F, McManus FP, Maarifi G, Chelbi-Alix MK, Thibault P. Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification. Nat Commun. 2017; 8:14109.
crossref
115. Lenschow DJ, Lai C, Frias-Staheli N, Giannakopoulos NV, Lutz A, Wolff T, Osiak A, Levine B, Schmidt RE, García-Sastre A, et al. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc Natl Acad Sci U S A. 2007; 104:1371–1376.
116. Ritchie KJ, Hahn CS, Kim KI, Yan M, Rosario D, Li L, de la Torre JC, Zhang DE. Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection. Nat Med. 2004; 10:1374–1378.
crossref
117. Ketscher L, Hannß R, Morales DJ, Basters A, Guerra S, Goldmann T, Hausmann A, Prinz M, Naumann R, Pekosz A, et al. Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance. Proc Natl Acad Sci U S A. 2015; 112:1577–1582.
118. Arimoto K, Konishi H, Shimotohno K. UbcH8 regulates ubiquitin and ISG15 conjugation to RIG-I. Mol Immunol. 2008; 45:1078–1084.
crossref
119. Lu G, Reinert JT, Pitha-Rowe I, Okumura A, Kellum M, Knobeloch KP, Hassel B, Pitha PM. ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradation. Cell Mol Biol (Noisy-le-grand). 2006; 52:29–41.
120. Shi HX, Yang K, Liu X, Liu XY, Wei B, Shan YF, Zhu LH, Wang C. Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification. Mol Cell Biol. 2010; 30:2424–2436.
crossref
121. Werneke SW, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, Vanlandingham DL, Higgs S, Fontanet A, Albert ML, et al. ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation. PLoS Pathog. 2011; 7:e1002322.
crossref
122. Bogunovic D, Byun M, Durfee LA, Abhyankar A, Sanal O, Mansouri D, Salem S, Radovanovic I, Grant AV, Adimi P, et al. Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency. Science. 2012; 337:1684–1688.
crossref
123. Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD, Yuan C, Volpi S, Li Z, Sanal O, Mansouri D, et al. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature. 2015; 517:89–93.
crossref
124. Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S, Speer SD, Li Z, van Unen L, Heijsman D, Goldmann T, et al. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med. 2016; 213:1163–1174.
crossref
125. Strebovsky J, Walker P, Lang R, Dalpke AH. Suppressor of cytokine signaling 1 (SOCS1) limits NFkappaB signaling by decreasing p65 stability within the cell nucleus. FASEB J. 2011; 25:863–874.
126. Chang PJ, Chen LW, Chen LY, Hung CH, Shih YJ, Wang SS. Effects of the NEDD8-activating enzyme inhibitor MLN4924 on lytic reactivation of Kaposi's sarcoma-associated herpesvirus. J Virol. 2017; 91:e00505–17.
crossref
127. Davis KA, Morelli M, Patton JT. Rotavirus NSP1 requires casein kinase II-mediated phosphorylation for hijacking of cullin-RING ligases. MBio. 2017; 8:e01213–17.
crossref
128. Ding S, Mooney N, Li B, Kelly MR, Feng N, Loktev AV, Sen A, Patton JT, Jackson PK, Greenberg HB. Comparative proteomics reveals strain-specific β-TrCP degradation via rotavirus NSP1 hijacking a host cullin-3-Rbx1 complex. PLoS Pathog. 2016; 12:e1005929.
crossref
129. Coleman KE, Békés M, Chapman JR, Crist SB, Jones MJ, Ueberheide BM, Huang TT. SENP8 limits aberrant neddylation of NEDD8 pathway components to promote cullin-RING ubiquitin ligase function. ELife. 2017; 6:e24325.
crossref
130. Noguchi K, Okumura F, Takahashi N, Kataoka A, Kamiyama T, Todo S, Hatakeyama S. TRIM40 promotes neddylation of IKKγ and is downregulated in gastrointestinal cancers. Carcinogenesis. 2011; 32:995–1004.
crossref
131. Yan F, Guan J, Peng Y, Zheng X. MyD88 NEDDylation negatively regulates MyD88-dependent NF-κB signaling through antagonizing its ubiquitination. Biochem Biophys Res Commun. 2017; 482:632–637.
crossref
132. Chan Y, Yoon J, Wu JT, Kim HJ, Pan KT, Yim J, Chien CT. DEN1 deneddylates non-cullin proteins in vivo. J Cell Sci. 2008; 121:3218–3223.
133. Mendoza HM, Shen LN, Botting C, Lewis A, Chen J, Ink B, Hay RT. NEDP1, a highly conserved cysteine protease that deNEDDylates Cullins. J Biol Chem. 2003; 278:25637–25643.
crossref
134. Wu K, Yamoah K, Dolios G, Gan-Erdene T, Tan P, Chen A, Lee CG, Wei N, Wilkinson KD, Wang R, et al. DEN1 is a dual function protease capable of processing the C terminus of Nedd8 and deconjugating hyper-neddylated CUL1. J Biol Chem. 2003; 278:28882–28891.
crossref
135. Kumari P, Kumar H. Viral deubiquitinases: role in evasion of anti-viral innate immunity. Crit Rev Microbiol.DOI: doi: 10.1080/1040841X.2017.1368999.
crossref
136. Zhao K, Zhang Q, Li X, Zhao D, Liu Y, Shen Q, Yang M, Wang C, Li N, Cao X. Cytoplasmic STAT4 promotes antiviral type I IFN production by blocking CHIP-mediated degradation of RIG-I. J Immunol. 2016; 196:1209–1217.
crossref
137. Ye JS, Kim N, Lee KJ, Nam YR, Lee U, Joo CH. Lysine 63-linked TANK-binding kinase 1 ubiquitination by mindbomb E3 ubiquitin protein ligase 2 is mediated by the mitochondrial antiviral signaling protein. J Virol. 2014; 88:12765–12776.
crossref
138. Yu Z, Song H, Jia M, Zhang J, Wang W, Li Q, Zhang L, Zhao W. USP1-UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses. J Exp Med. 2017; 214:3553–3563.
crossref
139. Cui J, Li Y, Zhu L, Liu D, Songyang Z, Wang HY, Wang RF. 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.
crossref
140. Saul VV, Niedenthal R, Pich A, Weber F, Schmitz ML. SUMO modification of TBK1 at the adaptor-binding C-terminal coiled-coil domain contributes to its antiviral activity. Biochim Biophys Acta. 2015; 1853:136–143.
crossref
141. Duong BH, Onizawa M, Oses-Prieto JA, Advincula R, Burlingame A, Malynn BA, Ma A. A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity. Immunity. 2015; 42:55–67.
crossref

Figure 1.
Virus-triggered PRRs-mediated signaling pathways leading to type I IFN and IL-1β induction.
in-18-e4f1.tif
Figure 2.
The C terminal conserved amino acids of ubiquitin and ubiquitin-like molecules.
in-18-e4f2.tif
Table 1.
Ubiquitin and ubiquitin-like modifications in virus-triggered PRRs-mediated signaling pathways
Target molecules E3 ligases-mediated ubiquitination Modification sites References
PRRs
   RIG-I RNF122 (K48 linkage) Lys115, Lys 146 Wang et al. (56)
  CHIP (K48 linkage) ND Zhao et al. (136)
  CypA-TRIM25 (K63 linkage) Lys172 Liu et al. (50)
  p97-RNF125 (K48 linkage) Lys181 Gack et al. (51) Hao et al. (55)
  TRIM40 (K27 and K48 linkage) ND Zhao et al. (59)
  Ube2D3, Ube2N (K63 linkage) Lys48, Lys96, Lys172 Shi et al. (52)
  MUL1 (SUMOylation) ND Doiron et al. (105)
  USP15 (K63 linkage) Zhang et al. (60)
  UbcH8 (ISGylation) ND Arimoto et al. (118)
  TRIM38 (SUMOylation) Lys96, Lys888 Hu et al. (106)
  SENP2
   MDA5 TRIM65 (K63 linkage) Lys743 Lang et al. (67)
  TRIM40 (K27 and K48 linkage) Lys23, Lys43, Lys68 Zhao et al. (59)
  PIAS2β (SUMOylation) ND Fu et al. (104)
  TRIM38 (SUMOylation) Lys43, Lys865 Hu et al. (106)
   cGAS RNF185 (K27 linkage) ND Wang et al. (68)
  TRIM38 (SUMOylation) Lys83, Lys231, Lys479 Hu et al. (107)
  SENP2
  SENP7 Lys335, Lys372, Lys382 Cui et al. (108)
  USP14 (K48 linkage) Lys414 Chen et al. (69)
   NLRP3 FBXL12 (K48 linkage) Lys689 Han et al. (71)
  MARCH7 (K48 linkage) ND Yan et al. (72)
   AIM2, IFI16 ND
Adaptor proteins
   TRIF TRIM38 (K48 linkage) Lys228 Xue et al. (73)
      Hu et al. (74)
  WWP2 (K48 linkage) ND Yang et al. (75)
  TRIM32 (ubiquitin-independent) Yang et al. (76)
   MyD88 CYLD (K63 linkage) Lys231 Lee et al. (77)
  Smurf1/2 (K48 linkage) Lys231, Lys262 Naiki et al. (78)
      Strickson et al. (79)
  Pellino (K48 linkage) ND Ji et al. (80)
  ND (NEDDylation) ND Yan et al. (131)
   VISA Tetherin-MARCH8 (K48 linkage) Lys7 Jin et al. (82)
  TRIM31 (K63 linkage) Lys10, Lys311, Lys461 Liu et al. (24)
  IRTKS-PCBP2 (SUMOylation) Xia et al. (21)
   MITA TRIM29 (K48 linkage) ND Xing et al. (83)
  MUL1 (K63 linkage) Lys224 Ni et al. (84)
  TRIM30α (K48 linkage) Lys275 Wang et al. (85)
  AMFR (K27 linkage) Wang et al. (25)
  USP21 (K27/63 linkage) Chen et al. (88)
  USP18-USP20 (K48 linkage) Zhang et al. (86)
  USP13 (K27 linkage) Sun et al. (87)
  TRIM38 (SUMOylation) Lys338 Hu et al. (107)
   ASC TRAF3 (K63 linkage) Lys174 Guan et al. (95)
   TRAF3, TRAF6 ERα (K48 linkage) ND Wang et al. (90)
  cIAP1/2 (K63 and K48 linkage) Mao et al. (89)
  USP25 (K48 linkage) Lin et al. (93)
  MYSM1 (K63 linkage) Panda et al. (94)
  HSCARG-OTUB1 (K48 linkage) Peng et al. (91)
Kinases and transcription factors
   TBK1 MIB2 (K63 linkage) ND Ye et al. (137)
  RNF128 (K63 linkage) Lys30, Lys401 Song et al. (98)
  USP1–UAF1 (K48 linkage) ND Yu et al. (138)
  DYRK2-DTX4 (K48 linkage) Lys670 Cui et al. (139)
      An et al. (96)
  ND (SUMOylation) Lys694 Saul et al. (140)
   IRF3 c-Cbl (K48 linkage) ND Zhao et al. (99)
  LUBAC (linear) Lys193, Lys313 Chattopadhyay et al. (100)
  ND (SUMOylation) Lys152 Kubota et al. (110)
  PIAS1 (SUMOylation) ND Li et al. (112)
  SENP2 Lys70, Lys87 Yang et al. (22)
  HERC5 (ISGylation) Lys193, Lys360, Lys366 Lu et al. (119)
      Shi et al. (120)
   IRF7 TRIM28 (SUMOylation) Lys444, Lys446 Liang et al. (111)
  ND (SUMOylation) Lys406 Kubota et al. (110)
  TRAF6 (K63 linkage) Lys44, Lys446, Lys452 Ning et al. (101)
   Pro-IL-1β A20 (K63 linkage, unanchored) Lys133 Duong et al. (141)

ND, not determined.

TOOLS
Similar articles