TRIM29 Negatively Controls Antiviral Immune Response Through Targeting STING for Degradation

Overview

Journal Cell Discov

Date 2018 Mar 28

PMID 29581886

Citations 63

Authors

Qijie Li

Liangbin Lin

Yanli Tong

Yantong Liu

Jun Mou

Xiaodong Wang

Xiuxuan Wang

Yanqiu Gong

Yi Zhao

Yi Liu

Bo Zhong

Lunzhi Dai

Yu-quan Wei

Huiyuan Zhang

Hongbo Hu

Affiliations

Soon will be listed here.

Abstract

Innate immune system is armed by several lines of pattern recognition receptors to sense various viral infection and to initiate antiviral immune response. This process is under a tight control and the negative feedback induced by infection and/or inflammation is critical to maintain immune homoeostasis and to prevent autoimmune disorders, however, the molecular mechanism is not fully understood. Here we report TRIM29, a ubiquitin E3 ligase, functions as an inducible negative regulator of innate immune response triggered by DNA virus and cytosolic DNA. DNA virus and cytosolic DNA stimulation induce TRIM29 expression robustly in macrophages and dendritic cells, although the basal level of TRIM29 is undetectable in those cells. TRIM29 deficiency elevates IFN-I and proinflammatory cytokine production upon viral DNA and cytosolic dsDNA stimulation. Consistently, in vivo experiments show that TRIM29-deficient mice are more resistant to HSV-1 infection than WT controls, indicated by better survival rate and reduced viral load in organs. Mechanism studies suggest that STING-TBK1-IRF3 signaling pathway in TRIM29 KO cells is significantly enhanced and the degradation of STING is impaired. Furthermore, we identify that TRIM29 targets STING for K48 ubiquitination and degradation. This study reveals TRIM29 as a crucial negative regulator in immune response to DNA virus and cytosolic DNA, preventing potential damage caused by overcommitted immune responses.

Citing Articles

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References

Kim M, Hwang S, Imaizumi T, Yoo J . Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J Virol. 2007; 82(3):1474-83. PMC: 2224411. DOI: 10.1128/JVI.01650-07. View

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408(6813):740-5. DOI: 10.1038/35047123. View

Hu H, Brittain G, Chang J, Puebla-Osorio N, Jin J, Zal A . OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3. Nature. 2013; 494(7437):371-4. PMC: 3578967. DOI: 10.1038/nature11831. View

Hu H, Wang H, Xiao Y, Jin J, Chang J, Zou Q . Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. J Exp Med. 2016; 213(3):399-414. PMC: 4813674. DOI: 10.1084/jem.20151426. View

Chiu Y, MacMillan J, Chen Z . RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell. 2009; 138(3):576-91. PMC: 2747301. DOI: 10.1016/j.cell.2009.06.015. View

Xing J, Weng L, Yuan B, Wang Z, Jia L, Jin R . Identification of a role for TRIM29 in the control of innate immunity in the respiratory tract. Nat Immunol. 2016; 17(12):1373-1380. PMC: 5558830. DOI: 10.1038/ni.3580. View

Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu Y . The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol. 2011; 12(10):959-65. PMC: 3671854. DOI: 10.1038/ni.2091. View

Liu L, Botos I, Wang Y, Leonard J, Shiloach J, Segal D . Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science. 2008; 320(5874):379-81. PMC: 2761030. DOI: 10.1126/science.1155406. View

Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks B, Schoenemeyer A . The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol. 2005; 175(8):5260-8. DOI: 10.4049/jimmunol.175.8.5260. View

10.

Kawai T, Akira S . Innate immune recognition of viral infection. Nat Immunol. 2006; 7(2):131-7. DOI: 10.1038/ni1303. View

11.

Sun L, Wu J, Du F, Chen X, Chen Z . Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2012; 339(6121):786-91. PMC: 3863629. DOI: 10.1126/science.1232458. View

12.

Rajsbaum R, Garcia-Sastre A, Versteeg G . TRIMmunity: the roles of the TRIM E3-ubiquitin ligase family in innate antiviral immunity. J Mol Biol. 2013; 426(6):1265-84. PMC: 3945521. DOI: 10.1016/j.jmb.2013.12.005. View

13.

Loo Y, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L . Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol. 2007; 82(1):335-45. PMC: 2224404. DOI: 10.1128/JVI.01080-07. View

14.

Sun W, Li Y, Chen L, Chen H, You F, Zhou X . ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A. 2009; 106(21):8653-8. PMC: 2689030. DOI: 10.1073/pnas.0900850106. View

15.

Orzalli M, DeLuca N, Knipe D . Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. Proc Natl Acad Sci U S A. 2012; 109(44):E3008-17. PMC: 3497734. DOI: 10.1073/pnas.1211302109. View

16.

Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M . The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004; 5(7):730-7. DOI: 10.1038/ni1087. View

17.

Fernandez-Trujillo M, Garcia-Rosado E, Alonso M, Castro D, Alvarez M, Bejar J . Mx1, Mx2 and Mx3 proteins from the gilthead seabream (Sparus aurata) show in vitro antiviral activity against RNA and DNA viruses. Mol Immunol. 2013; 56(4):630-6. DOI: 10.1016/j.molimm.2013.06.018. View

18.

Shu H, Wang Y . Adding to the STING. Immunity. 2014; 41(6):871-3. DOI: 10.1016/j.immuni.2014.12.002. View

19.

Hu M, Yang Q, Xie X, Liao C, Lin H, Liu T . 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(3):555-569. DOI: 10.1016/j.immuni.2016.08.014. View

20.

Takaoka A, Wang Z, Choi M, Yanai H, Negishi H, Ban T . DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature. 2007; 448(7152):501-5. DOI: 10.1038/nature06013. View