TBK1-NQO1 negative feedback loop regulates antiviral innate immunity

TANK-binding kinase 1 (TBK1) is an essential kinase that phosphorylates transcriptional factors, which induce antiviral interferons and inflammatory cytokines against viral infection. Tight regulation of TBK1 is critical for innate immune responses and maintenance of homeostasis. Here, we report that NAD(P)H: quinone-oxidoreductase-1 (NQO1) forms a negative feedback loop with TBK1 to regulate innate antiviral immune responses. At the late time stages of virus infection, NQO1 specifically interacts with TBK1 and is phosphorylated at S82 of NQOI by TBK1. Interestingly, S82-phosphorylated NQO1 interferes with the self-association and phosphorylation of TBK1, resulting in reduced type I IFN signaling cascades. Depletion or reduced expression of NQO1 increases secretion of antiviral cytokines and resultes in less viral replication. In particular, NQO1−/− mice are more resistant to viral infection due to the enhanced secretion of antiviral cytokines. Taken together, these finding provide new insight into the molecular regulation of NQOI and TBK1 and suggest a critical role for NQOI in the homeostatic control of antiviral response and innate immune responses.