Porcine Epidemic Diarrhea Virus nsp7 Inhibits MDA5 Dephosphorylation to Antagonize Type I Interferon Production

• DOI: 10.1128/spectrum.05017-22
• Publication Date: 2023-03-28T14:01:18Z
• Authors: Jiansong Zhang; Puxian Fang; Jie Ren; Sijin Xia; Huichang Zhang; Xuerui Zhu; Tong Ding; Shaobo Xiao; Liurong Fang
• Keywords: Coronavirus; MDA5; Dephosphorylation; IRF3

Porcine epidemic diarrhea virus (PEDV) is a reemerging enteropathogenic coronavirus that causes high mortality in piglets and has catastrophic effects on the global pig industry. PEDV-encoded nonstructural protein 7 (nsp7) an important component of viral replication transcription complex, previous study reported it inhibits poly(I:C)-induced type I interferon (IFN) production, but mechanism by which this occurs remains unclear. Here, we demonstrated ectopic expression PEDV nsp7 antagonized Sendai (SeV)-induced beta (IFN-β) as well activation factors regulatory factor 3 (IRF3) nuclear factor-kappa B (NF-κB) both HEK-293T LLC-PK1 cells. Mechanistically, targets melanoma differentiation-associated gene 5 (MDA5) interacts with its caspase recruitment domains (CARDs), sequester interactions between MDA5 phosphatase 1 (PP1) catalytic subunits (PP1α PP1γ), thereby suppressing S828 dephosphorylation keeping inactive. Furthermore, infection attenuated multimerization MDA5-PP1α/-γ interactions. We also tested orthologs five other mammalian coronaviruses found all them except severe acute respiratory syndrome 2 (SARS-CoV-2) inhibited SeV- or MDA5-induced IFN-β production. Collectively, these results suggest inhibition may be common strategy employed some to antagonize MDA5-mediated IFN IMPORTANCE Since late 2010, porcine variant pathogenesis swept through most farms many countries, resulting significant economic losses. Coronavirus (nsp7), conserved within family Coronaviridae, combines nsp8 nsp12 form complex indispensable for replication. However, function largely unknown. Our present demonstrates specifically competes PP1 binding impedes PP1-mediated at S828, blocking revealing utilized efficiently escape host innate immunity.