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PLP2, a potent deubiquitinase from murine hepatitis virus, strongly inhibits cellular type I interferon production

Dahai Zheng1, Gang Chen, Beichu Guo

  • 1Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 15 Da Tun Road, Chaoyang District, Beijing 100101, China.

Cell Research
|October 30, 2008
PubMed

Insights

Coronaviruses evade host immunity by suppressing type I interferon production. This study identifies a viral protease, Papain-like protease domain 2 (PLP2), that inhibits interferon signaling by deubiquitinating IRF3.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Coronaviruses, including SARS-CoV, cause limited type I interferon (IFN) production, linked to severe disease.
  • The precise molecular mechanisms behind this suppressed IFN response in coronavirus infections are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which coronaviruses inhibit host type I interferon production.
  • To identify specific viral factors involved in evading innate antiviral responses.

Main Methods:

  • Investigated the interaction between the coronavirus nonstructural protein 3 (nsp3) Papain-like protease domain 2 (PLP2) and IRF3.
  • Assessed the effect of PLP2 on IRF3 ubiquitination and nuclear translocation using co-expression systems.
  • Measured IFN-beta reporter gene activity upon co-expression of PLP2 and components of the IFN signaling pathway (CARDIF, TBK1, IRF3).
  • Evaluated the impact of wild-type and catalytically inactive PLP2 on viral replication (VSV) and IFN induction in infected cells.

Main Results:

  • Papain-like protease domain 2 (PLP2) of MHV-A59 binds to IRF3, promoting its deubiquitination.
  • PLP2 inhibits the nuclear translocation of IRF3, a key transcription factor for IFN production.
  • Co-expression of PLP2 significantly suppresses IFN-beta reporter activity mediated by CARDIF, TBK1, and IRF3.
  • Wild-type PLP2, but not a mutant lacking deubiquitinase (DUB) activity, reduces IFN induction and enhances viral growth in VSV-infected cells.

Conclusions:

  • Uncovered a viral deubiquitinase (DUB) activity within the coronavirus PLP2 domain.
  • Coronaviruses likely utilize this PLP2 DUB to interfere with IRF3 activation and evade host innate antiviral immunity.
  • This finding provides a molecular explanation for the impaired IFN response observed in coronavirus infections.

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