PLP2, a potent deubiquitinase from murine hepatitis virus, strongly inhibits cellular type I interferon production.
Infections by coronaviruses such as severe acute respiratory syndrome (SARS) coronavirus (SCoV) and mouse hepatitis virus A59 (MHV-A59) result in very little type I interferon (IFN) production by host cells, which is potentially responsible for the rapid viral growth and severe immunopathology associated with SARS. However, the molecular mechanisms for the low IFN production in cells infected with coronaviruses remain unclear. Here, we provide evidence that Papain-like protease domain 2 (PLP2), a catalytic domain of the nonstructural protein 3 (nsp3) of MHV-A59, can bind to IRF3, cause its deubiquitination and prevent its nuclear translocation. As a consequence, co-expression of PLP2 strongly inhibits CARDIF-, TBK1- and IRF3-mediated IFNbeta reporter activities. In addition, we show that wild-type PLP2 but not the mutant PLP2 lacking the deubiquitinase (DUB) activity can reduce IFN induction and promote viral growth in cells infected with VSV. Thus, our study uncovered a viral DUB which coronaviruses may use to escape from the host innate antiviral responses.
Zheng
Dahai
D
Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 15 Da Tun Road, Chaoyang District, Beijing 100101, China.
Chen
Gang
G
Guo
Beichu
B
Cheng
Genhong
G
Tang
Hong
H
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D017934:Coronavirus / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism*; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D006517:Murine hepatitis virus / Q000235:genetics* / Q000378:metabolism*; D010206:Papain / Q000378:metabolism; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000378:metabolism; D045169:Severe Acute Respiratory Syndrome / Q000235:genetics / Q000378:metabolism / Q000821:virology; D054875:Ubiquitination; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism*
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016898:Interferon-alpha; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta; D010206:Papain