SARS‐CoV‐2 ORF6 protein targets IFP35 to inhibit the IFNγ signaling pathway

Abstract The innate immune system functions as the frontline barrier against invading pathogens, such as severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). Nevertheless, the virus has developed various strategies to effectively regulate host immune responses, particularly through the inhibition of interferon signaling. In this study, we identify the SARS‐CoV‐2 accessory protein ORF6 as a key inhibitor of interferon gamma (IFNγ) signaling through downregulation of the interferon‐induced 35‐kDa protein (IFP35). IFP35 , an interferon‐stimulated gene (ISG) critical for interferon ‐mediated antiviral response, is significantly upregulated during SARS‐CoV‐2 infection. Silencing IFP35 via RNA interference enhances viral replication, indicating its antiviral role. Furthermore, we demonstrate that ORF6 associates with IFP35 and accelerates its ubiquitin–proteasome degradation, thereby impairing IFP35's ability to activate IFNγ signaling. These data reveal novel mechanisms used by SARS‐CoV‐2 to circumvent host immunity, specifically by impairing IFNγ signaling.