Negative feedback regulation of cellular antiviral signaling by RBCK1-mediated degradation of IRF3.
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.
Zhang
Min
M
College of Life Sciences, Peking University, Beijing 100871, China.
Tian
Yang
Y
Wang
Rui-Peng
RP
Gao
Dong
D
Zhang
Yan
Y
Diao
Fei-Ci
FC
Chen
Dan-Ying
DY
Zhai
Zhong-He
ZH
Shu
Hong-Bing
HB
D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics*; D007370:Interferon Type I / Q000276:immunology; D029082:Sendai virus / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D014157:Transcription Factors; D025801:Ubiquitin; C504507:RBCK1 protein, human; D044767:Ubiquitin-Protein Ligases