title: Middle east respiratory syndrome coronavirus 4a protein is a double-stranded RNA-binding protein that suppresses PACT-induced activation of RIG-I and MDA5 in the innate antiviral response.
abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging pathogen that causes severe disease in human. MERS-CoV is closely related to bat coronaviruses HKU4 and HKU5. Evasion of the innate antiviral response might contribute significantly to MERS-CoV pathogenesis, but the mechanism is poorly understood. In this study, we characterized MERS-CoV 4a protein as a novel immunosuppressive factor that antagonizes type I interferon production. MERS-CoV 4a protein contains a double-stranded RNA-binding domain capable of interacting with poly(I · C). Expression of MERS-CoV 4a protein suppressed the interferon production induced by poly(I · C) or Sendai virus. RNA binding of MERS-CoV 4a protein was required for IFN antagonism, a property shared by 4a protein of bat coronavirus HKU5 but not by the counterpart in bat coronavirus HKU4. MERS-CoV 4a protein interacted with PACT in an RNA-dependent manner but not with RIG-I or MDA5. It inhibited PACT-induced activation of RIG-I and MDA5 but did not affect the activity of downstream effectors such as RIG-I, MDA5, MAVS, TBK1, and IRF3. Taken together, our findings suggest a new mechanism through which MERS-CoV employs a viral double-stranded RNA-binding protein to circumvent the innate antiviral response by perturbing the function of cellular double-stranded RNA-binding protein PACT. PACT targeting might be a common strategy used by different viruses, including Ebola virus and herpes simplex virus 1, to counteract innate immunity.
  
  
  OBJECTIVE
  Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging and highly lethal human pathogen. Why MERS-CoV causes severe disease in human is unclear, and one possibility is that MERS-CoV is particularly efficient in counteracting host immunity, including the sensing of virus invasion. It will therefore be critical to clarify how MERS-CoV cripples the host proteins that sense viruses and to compare MERS-CoV with its ancestral viruses in bats in the counteraction of virus sensing. This work not only provides a new understanding of the abilities of MERS-CoV and closely related bat viruses to subvert virus sensing but also might prove useful in revealing new strategies for the development of vaccines and antivirals.
authors: Department of Biochemistry, University of Hong Kong, Pokfulam, Hong Kong.
authors: Kam-Leung
authors: KL
authors: Siu
authors: Man Lung
authors: ML
authors: Yeung
authors: Kin-Hang
authors: KH
authors: Kok
authors: Kit-San
authors: KS
authors: Yuen
authors: Chun
authors: C
authors: Kew
authors: Pak-Yin
authors: PY
authors: Lui
authors: Chi-Ping
authors: CP
authors: Chan
authors: Herman
authors: H
authors: Tse
authors: Patrick C Y
authors: PC
authors: Woo
authors: Kwok-Yung
authors: KY
authors: Yuen
authors: Dong-Yan
authors: DY
authors: Jin
mesh_terms: D002460:Cell Line; D017934:Coronavirus / Q000276:immunology*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011971:Receptors, Immunologic; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C104647:PRKRA protein, human; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D014764:Viral Proteins; D007372:Interferons; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1