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Interferons Command Trim22 to Fight Against Viruses Cellular & Molecular Immunology (2017) 14, 794–796 & 2017 CSI and USTC All rights reserved 2042-0226/17 $32.00 www.nature.com/cmi LETTER TO THE EDITOR Interferons command Trim22 to fight against viruses Qiaoshi Lian1,2 and Bing Sun1 Cellular & Molecular Immunology (2017) 14, 794–796; doi:10.1038/cmi.2017.76; published online 7 August 2017 he mammalian innate immune sys- infection, leading to liver cirrhosis or Trim22 is an IFN-inducible protein Ttem provides the first line of defen- even hepatocellular carcinoma.3 HCV is that is induced by IFN-α and IFN-γ in sive mechanisms to protect the host an enveloped, positive-sense single- HepG2 cells, an epithelial-like human against invading pathogens. These defen- stranded RNA virus. The genome of liver carcinoma cell line.10 Yang et al. sive responses are initiated by recogni- HCV encodes structural proteins (core, validated the inducible expression of tion of microbial pathogen-associated E1 and E2) and nonstructural proteins trim22 by IFN-α in Huh-7 cells. The molecular patterns (PAMPs), which are (p7, nonstructural (NS) 2, NS3, NS4A, authors presented a direct induction of engaged by conserved germline-encoded NS4B, NS5A and NS5B). During HCV trim22 by HCV infection after 24 h in pattern recognition receptors (PRRs).1 infection, viral dsRNA replicative inter- Huh-7 cells; however, the upregulation Viral infection is always a considerable mediates can be recognized by RIG-I and of trim22 was lower than that noted with threat for public health. During viral MDA5 to induce a type I IFN response, IFN treatment. In addition, the study infection, viral nucleic acids serve as the which is crucial for the host to counter- demonstrated that trim22 was signifi- dominant PAMPs for the host innate act HCV infection.4,5 cantly induced in PBMCs of HCV- immune system, which can be recog- The tripartite motif (TRIM) family is a infected patients following IFN-α treat- nized by diverse PRR families, including well-known superfamily with Ring-finger ment. In addition, trim22 expression Toll-like receptors (TLRs), RIG-I-like E3 ubiquitin ligase activity. The TRIM peaked at 12 h post IFN-α treatment, receptors and cytosolic DNA receptors. family includes greater than 70 members suggesting a potential role of trim22 in α Viral nucleic acid sensing markedly trig- in humans. TRIM family members have IFN- -mediated anti-HCV therapy. gers downstream type I interferon secre- been implicated as critical regulators of Using a reconstructed Huh-7 cell line tion, which thereby activates interferon- innate immune responses against micro- stably expressing the HCV Con1 replicon stimulated genes to exert anti-viral bial pathogens, including anti-viral genome, the authors assessed the anti- 6,7 effects.2 responses. Virus recognition-triggered HCV activity of trim22. Overexpression Hepatitis C virus (HCV) is a danger- type I interferon could subsequently of trim22 markedly inhibited HCV ous human pathogen that infects over induce numerous TRIM proteins expres- NS5A protein levels and HCV replicon 170 million individuals worldwide. HCV sion, which are crucial for restricting levels, and trim22 knockdown greatly infection easily develops into a persistent viral infection via either regulating innate enhanced HCV replication activity that signaling pathways or serving as viral occurred upon IFN treatment but not at 8 1State Key Laboratory of Cell Biology, CAS Center restriction factors. Trim22 is a typical steady state. for Excellence in Molecular Cell Science, Shang- TRIM family protein that restricts the Assessment of the mechanism indi- hai Institute of Biochemistry and Cell Biology, replication of various viruses via distinct cated that trim22 directly interacted with Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai manners, for example, inhibiting HIV NS5A. NS5A is an HCV nonstructural 200031, China and 2University of Chinese Acad- particle production,9 suppressing the protein that is critical for both HCV emy of Sciences, Beijing 100049, China activity of hepatitis B virus core replication and assembly.13 The crosstalk Correspondence: Professor B Sun, PhD, State 10 fl Key Laboratory of Cell Biology, CAS Center for promoter and targeting in uenza A of host factors and viral factors is a Excellence in Molecular Cell Science, Shanghai virus nucleoprotein for degradation.11 consequence of co-evolution. Viral fac- Institute of Biochemistry and Cell Biology, In our previous work, Yang et al.12 tors typically target host factors to avoid Chinese Academy of Sciences, 320 Yueyang identified the anti-viral role of trim22 immune sensing or immune clearance. Road, Shanghai 200031, China. E-mail: [email protected] on the inhibition of HCV replication Conversely, many host factors can also Received: 30 June 2017; Accepted: 1 July 2017 (Figure 1). bind to viral factors to restrict viral Interferons command Trim22 to fight against viruses QLianandBSun 795 Figure 1 Trim22 is a broad anti-viral host factor. During virus infection, including HIV, HBV, influenza A virus and HCV, viral nucleic acids are detected by host PRRs (such as TLR3/7/8/9, RIG-I/MDA5, cGAS/DDX41/IFI16). Recognition of viral DNA/RNA triggers type I interferon production dependent on IRF3 activation. Secreted IFN-α/β bind to IFNAR to activate the Stat1-Stat2 heterodimer to induce the expression of trim22, a critical viral restriction factor, protecting the host against diverse viral infections. replication. NS5A targets Myd88 to activity of HCV replication was deter- HCV infections are associated with spe- attenuate TLR signaling and interacts mined by a Huh-7-Con1-rep cell system cial TRIM22 SNPs in the clinic.14 The with PKR to interfere with HCV RNA rather than direct HCV infection. Thus, reported viruses targeted by trim22 vary replication.13 However, few host factors whether trim22 indeed restricts HCV from RNA viruses to DNA viruses and have been identified as targeting NS5A. virus infection in vivo remains to be single-strand viruses to double-strand et al. fi Here Yang identi ed interactions further validated. Another important viruses, displaying little specificity. More with trim22 and NS5A via SPRY domain question involves evaluating trim22 interestingly, trim22 restricts the infec- and domain 1, respectively. The interac- expression levels in healthy donors and tion of these viruses through largely tion rendered trim22 as an ubiquitin HCV-infected patients to determine distinct mechanisms. Hence, trim22 is a ligase of NS5A. Overexpression of trim22 whether HCV infection induces trim22 broad and multifunctional host anti-viral specifically decreased NS5A protein levels upregulation in vivo. Following this factor induced by interferons. rather than other HCV structural or study, another group confirmed the nonstructural proteins. Moreover, endo- protective role of trim22 against HCV CONFLICT OF INTEREST genous NS5A could be ubiquitinated by and uncovered the clinical significance of The authors declare no conflict of interest. trim22. IFN treatment induced ubiquiti- trim22 for IFN-α-mediated HCV ther- nation of endogenous NS5A. However, apy. Medrano et al. analyzed whether the authors did not map the ubiquitina- single nucleotide polymorphisms (SNPs) TRIM22 TRIM5 tion type and ubiquitination site of NS5A at and genes were 1 Broz P, Monack DM. Newly described pat- by E3 ligase trim22, which is crucial to associated with liver fibrosis and tern recognition receptors team up against understand the regulatory mechanism of response to IFN-α plus ribavirin therapy intracellular pathogens. Nat Rev Immunol 2013; 13:551–565. trim22 on HCV infection. Overall, the in HIV/HCV co-infected patients. The 2 Yan N, Chen ZJ. Intrinsic antiviral immunity. study provides molecular insights to TRIM22 rs1063303 GG genotype is a Nat Immunol 2012; 13:214–222. better understand IFN-α-mediated sensitive SNP for liver fibrosis in HIV/ 3 Lavanchy D. The global burden of hepatitis – HCV infection therapy. HCV co-infected patients.14 C. Liver Int 2009; 29:74 81. 4 Hei L, Zhong J. Laboratory of genetics and Some important questions that arise Notably, trim22 is crucial for the physiology 2 (LGP2) plays an essential role from this study should be further restriction of infection by diverse viruses, in hepatitis C virus infection-induced inter- fl feron responses. Hepatology 2017; 65: explored. What is the restriction activity including HIV, in uenza A virus, HBV, – 15 1478 1491. of trim22 against HCV infection? The herpesvirus and HCV (Figure 1). 5 Cao X, Ding Q, Lu J, Tao W, Huang B, Zhao Y present trim22-mediated inhibition Among these viruses, HIV, HBV and et al. MDA5 plays a critical role in interferon Cellular & Molecular Immunology Interferons command Trim22 to fight against viruses QLianandBSun 796 response during hepatitis C virus infection. Production by Induction of TRIM22. PLoS 13 Wong M-T, Chen SSL. Emerging roles of J Hepatol 62:771–778. Pathog 2008; 4: e1000007. interferon-stimulated genes in the innate 6 Kawai T, Akira S. Regulation of innate 10 Gao B, Duan Z, Xu W, Xiong S. Tripartite immune response to hepatitis C virus infec- immune signalling pathways by the tripartite motif-containing 22 inhibits the activity of tion. Cell Mol Immunol 2016; 13:11–35. motif (TRIM) family proteins. EMBO Mol hepatitis B virus core promoter, which is 14 Medrano LM, Rallón N, Berenguer J, Jimé- – Med 2011; 3:513 527. dependent on nuclear-located RING domain. nez-Sousa MA, Soriano V, Aldámiz-Echevar- 7 Versteeg Gijs A, Rajsbaum R, Sánchez-Apar- Hepatology 2009; 50:424–433. ria T et al. Relationship of TRIM5 and icio Maria T, Maestre Ana M, Valdiviezo J, 11 Di Pietro A, Kajaste-Rudnitski A, Oteiza A, TRIM22 polymorphisms with liver disease Shi M et al. The E3-ligase TRIM family of Nicora L, Towers GJ, Mechti N et al. and HCV clearance after antiviral therapy in proteins regulates signaling pathways trig- TRIM22 inhibits influenza A virus infection gered by innate immune pattern-recognition HIV/HCV coinfected patients.
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