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TRIM21 Is Essential to Sustain IFN Regulatory Factor 3 Activation during Antiviral Response¹

Kai Yang^2,*, He-Xin Shi^2,*, Xin-Yi Liu^2,*, Yu-Fei Shan^*, Bo Wei^*, She Chen and Chen Wang^3,*

^* Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and Mass Spectrometric Center, National Institute of Biological Sciences, Beijing, China

Virus infection induces host antiviral responses including induction of type I IFNs. Transcription factor IFN regulatory factor 3 (IRF3) plays an essential role and is tightly regulated in this process. Herein we report that TRIM21 (tripartite motif-containing 21) is significantly induced and interacts with IRF3 upon RNA virus infection. Ectopic expression or knockdown of TRIM21 could respectively enhance or impair IRF3-mediated gene expression. Mechanistically, TRIM21 interferes with the interaction between Pin1 (peptidyl-prolyl cis/trans isomerase, NIMA-interacting 1) and IRF3, thus preventing IRF3 ubiquitination and degradation. A conserved motif in the B 30.2 domain of TRIM21 is critical for its modulation of IRF3 function, while the RING finger is dispensable. Host antiviral responses are significantly boosted or crippled in the presence or absence of TRIM21. Our results identify TRIM21 as an essential modulator of IRF3 stability and demonstrate that it positively regulates the strength and duration of primary antiviral response, thus further strengthening the notion that the TRIM family is evolutionarily integrated with innate immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Natural Science Foundation of China (30570378, 30225013); the Ministry of Science and Technology of China (2007CB914504, 2006CB504301, 2006AA02Z121), and the Chinese Academy of Sciences (KSCX1-YW-R-06).

² K.Y., H.-X.S., and X.-Y.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Chen Wang, Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China. E-mail address: cwang01{at}sibs.ac.cn

⁴ Abbreviations used in this paper: PRR, pattern recognition receptor; HA, hemagglutinin; IRF3, IFN regulatory factor 3; IKK, NF-B inhibitor kinase ; MDA5, melanoma differentiation-associated gene 5; MOI, multiplicity of infection; NC, nonspecific control; NDV-GFP, Newcastle disease virus-GFP; PAMP, pathogen-associated molecular pattern; Pin1, peptidyl-prolyl cis/trans isomerase, NIMA-interacting 1; RIG-I, retinoic acid-inducible gene I; RNF125, RING finger protein 125; SeV, Sendai virus; TBK1, TANK-binding kinase 1; TRIM21, tripartite motif-containing 21; Ub, ubiquitin; VSV, vesicular stomatitis virus.

⁵ The online version of this article contains supplemental material.

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