Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6.
Ubiquitination and deubiquitination have emerged as critical post-translational regulatory mechanisms for activation or attenuation of the virus-triggered type I interferon (IFN)(2) induction pathways. In this study, we identified two deubiquitinating enzymes, OTUB1 and OTUB2, as negative regulators of virus-triggered type I IFN induction. Overexpression of OTUB1 and OTUB2 inhibited virus-induced activation of IRF3 and NF-kappaB, transcription of the IFNB1 gene as well as cellular antiviral response, whereas knockdown of OTUB1 and OTUB2 had opposite effects. Coimmunoprecipitations indicated OTUB1 and -2 interacted with TRAF3 and TRAF6, two E3 ubiquitin ligases required for virus-triggered IRF3 and NF-kappaB activation, respectively. Furthermore, we found that OTUB1 and OTUB2 mediated virus-triggered deubiquitination of TRAF3 and -6. These findings suggest that OTUB1 and OTUB2 negatively regulate virus-triggered type I IFN induction and cellular antiviral response by deubiquitinating TRAF3 and -6.
Li
Shu
S
College of Life Sciences, Modern Virology Center, Wuhan University, Wuhan 430072, China.
Zheng
Hao
H
Mao
Ai-Ping
AP
Zhong
Bo
B
Li
Ying
Y
Liu
Yu
Y
Gao
Yan
Y
Ran
Yong
Y
Tien
Po
P
Shu
Hong-Bing
HB
D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016328:NF-kappa B; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; C496399:OTUB2 protein, human; D013869:Thiolester Hydrolases; D000072017:Deubiquitinating Enzymes; C538826:OTUB1 protein, human; D003546:Cysteine Endopeptidases