HSPA2 modulates antiviral immunity by inhibiting TBK1 activation

The production of type I interferons (IFN-I) induced by viruses is critical for the host to resist viral infection. While emerging studies have implicated heat shock protein A2 (HSPA2) in various diseases, its specific role in antiviral immunity remains elusive. Here, using Hspa2-deficient mice and cellular models, we demonstrate that HSPA2 negatively regulates IFN-I production by targeting TANK-binding kinase 1 (TBK1). Mechanistically, HSPA2 binds to TBK1 and competes with the HECT and RLD domains containing E3 ubiquitin protein ligase 5 (HERC5) for TBK1 binding, thereby abrogating HERC5-dependent K63-linked ubiquitination of TBK1 at lysine 608 (K608), which disrupts the formation of TBK1-associated complexes and suppresses the subsequent dimerization and nuclear translocation of interferon regulatory factor 3 (IRF3), ultimately blocking IFN-I production. This study provides insights into the regulatory network governing innate immune homeostasis and identifies HSPA2 as a potential target for antiviral therapy.