1. ¹Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 15 Da Tun Road, Chaoyang District, Beijing 100101, China;
2. ²Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA;
3. ³Graduate University of Chinese Academy of Sciences, 19 Yu Quan Road, Shijingshan District, Beijing 100049, China

Correspondence: Hong Tang, Tel: +86-10-64888438; Fax: +86-10-64848357 E-mail: tanghong@moon.ibp.ac.cn; Genhong Cheng, Tel: +1-310-825-8896; Fax: +1-310-206-5553 E-mail: gcheng@mednet.ucla.edu

Received 12 July 2008; Revised 12 August 2008; Accepted 1 September 2008.

Abstract

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 IFN 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.