Factor inhibiting HIF negatively regulates antiviral innate immunity via hydroxylation of IKK

Activation of type I interferon (IFN-1) signaling is essential to protect host cells from viral infection. The full spectrum of IFN-I induction requires the activation of a number of cellular factors, including IkB kinase epsilon (IKKE). However, the regulation of IKKE activation in response to viral infection remains largely unknown. Here, we show that factor inhibiting hypoxia-inducible factor (HIF) (FIH), an asparaginyl hydroxylase, interacts with IKKE and catalyzes asparagine hydroxylation of IKKE at Asn-254, Asn-700, and Asn-701, resulting in the suppression of IKKE activation. FIH-mediated hydroxylation of IKKE prevents IKKE binding to TBK1 and TRAF3 and attenuates the cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex-catalyzed K63-linked polyubiquitination of IKKE at Lys-416. In addition, Fih-deficient mice and zebrafish are more resistant to viral infection. This work uncovers a previously unrecognized role of FIH in suppressing IKKE activation for IFN signaling and antiviral immune responses.