The CD97-PPM1G axis dampens antiviral immunity by dephosphorylating IRF7 in type I interferon pathway

The activation of type I interferon (IFN-I) signaling is crucial for defending host cells against viral infections. A comprehensive IFN-I response necessitates the activation of several cellular factors, among them Interferon Regulator Factor 7 (IRF7). Nonetheless, the mechanisms governing IRF7 inactivation in response to viral infection remain largely unknown. Here, we illustrate that Cluster of differentiation 97 (CD97), a G protein-coupled receptor, interacts with PPM1G via intracellular Arg-819 and Arg-822 residues. PPM1G then recruits and dephosphorylates IRF7, leading to its inhibition. CD97-mediated inactivation of IRF7 impedes its translocation into the nucleus and subsequent activation of IFN-I, ultimately promoting the viral replication. Moreover, mice lacking CD97 display heightened resistance to viral infection. The compound sanguinarine (SANG) hinders viral replication by dampening CD97 expression. This study provides a basis for CD97 as a potential antiviral target and SANG as a candidate antiviral small molecule drug.