Negative feedback regulation of cellular antiviral signaling by RBCK1-mediated degradation of IRF3

doi:doi:10.1038/cr.2008.277

Cell Research (2008) 18:1096–1104. doi: 10.1038/cr.2008.277; published online 19 August 2008

Negative feedback regulation of cellular antiviral signaling by RBCK1-mediated degradation of IRF3

Min Zhang¹, Yang Tian¹, Rui-Peng Wang¹, Dong Gao¹, Yan Zhang¹, Fei-Ci Diao¹, Dan-Ying Chen¹, Zhong-He Zhai¹ and Hong-Bing Shu²

¹College of Life Sciences, Peking University, Beijing 100871, China
²College of Life Sciences, Wuhan University, Wuhan 430072, China

Correspondence: Hong-Bing Shu, Tel: +86-27-68753795; Fax: +86-27-68753780 E-mail: shuh@whu.edu.cn; Dan-Ying Chen, Tel: +86-10-62757924; Fax: +86-10-62757924 E-mail: dychen@pku.edu.cn

Received 17 March 2008; Revised 14 May 2008; Accepted 17 June 2008.

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Abstract

Viral infection causes host cells to produce type I interferons (IFNs), which are critically involved in viral clearance. Previous studies have demonstrated that activation of the transcription factor interferon regulatory factor (IRF)3 is essential for virus-triggered induction of type I IFNs. Here we show that the E3 ubiquitin ligase RBCC protein interacting with PKC1 (RBCK1) catalyzes the ubiquitination and degradation of IRF3. Overexpression of RBCK1 negatively regulates Sendai virus-triggered induction of type I IFNs, while knockdown of RBCK1 has the opposite effect. Plaque assays consistently demonstrate that RBCK1 negatively regulates the cellular antiviral response. Furthermore, viral infection leads to induction of RBCK1 and subsequent degradation of IRF3. These findings suggest that the cellular antiviral response is controlled by a negative feedback regulatory mechanism involving RBCK1-mediated ubiquitination and degradation of IRF3.

Keywords:

RBCK1, IRF3, antiviral response, type I IFNs, feedback regulation, E3 ligase

Abbreviations:

NF- kappa B, (nuclear factor kappa B); IRF, (interferon regulatory factor); ISRE, (IFN-stimulated response elements); CARD, (caspase recruitment domain); TBK1, (TANK-binding kinase 1); IKK alt epsilon , (inhibitor of nuclear factor kappa B kinase subunit epsilon); RIG-I, (retinoic acid-inducible gene I); MDA5, (melanoma differentiation associated protein-5); SeV, (Sendai virus); RBCK1, (RBCC protein interacting with PKC1)