HSPA6 is induced by RIG-I-like receptors and negatively regulates type-I interferon signaling

The RIG-I-like receptors (RLRs) assemble into filamentous structures that initiate type-I interferon (IFN-I) and NF-κB signaling pathways via the adaptor protein MAVS and subsequent downstream signaling cascades. The formation and regulation of these filaments are influenced by numerous cellular proteins and complexes. In this study, we identified the stress-responsive heat shock protein HSPA6, which is induced upon RLR activation and acts as a negative regulator of IFN-I signaling. The expression of HSPA6 is independent of MAVS or IRF3 but is dependent on the E3 ligases associated with RLRs, stress granules (SGs), and the transcription factors IRF1 and AP-1. HSPA6 downregulates RLR-mediated IFN signaling by binding to these receptors in the cytoplasm and disrupting the formation of multimer complexes. Collectively, our findings reveal a novel feedback mechanism by RLRs that is distinct from the canonical IRF3-dependent IFN-I activation or NF-κB-mediated inflammatory cytokine induction.