Sec10 negatively regulates antiviral immunity by downregulating NRF2-ATF4-RIG-I axis.

Sec10, as a central component of the eight-protein exocyst complex, plays a crucial role in the exocytosis. However, its role in antiviral immunity has remained elusive. Here, we discover that Sec10 negatively regulates antiviral immune response by downregulation of RIG-I at transcriptional level, thereby facilitating RNA replication in multiple cells. Mechanistically, we demonstrate that ATF4 binds to the RIG-I promoter and promotes RIG-I transcription, and NRF2 upregulates ATF4 activity and expression. Notably, Sec10 triggers the inactivation of the NRF2-ATF4 axis during RNA viral infection, which is, in turn restrains RIG-I transcription, attenuating antiviral IFN-I response. Importantly, Sec10 deficiency results in enhanced innate immunity, diminished SeV load and morbidity in mice. Taken together, we firstly unveil the function of Sec10 in viral infection, and elucidate its novel mechanisms of antiviral immunity via the NRF2-ATF4-RIG-I axis, which provides the potential therapeutic targets and offers new insights for antiviral drug development.