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

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.