XAF1 prevents hyperproduction of type I interferon upon viral infection by targeting IRF7

Abstract Interferon regulatory factor (IRF) 3 and IRF7 are master regulators of type I interferon (IFN‐I)‐dependent antiviral innate immunity. Upon viral infection, a positive feedback loop is formed, wherein IRF7 promotes further induction of IFN‐I in the later stage. Thus, it is critical to maintain a suitably low level of IRF7 to avoid the hyperproduction of IFN‐I. In this study, we find that early expression of IFN‐I‐dependent STAT1 promotes the expression of XAF1 and that XAF1 is associated specifically with IRF7 and inhibits the activity of XIAP. XAF1‐knockout and XIAP‐transgenic mice display resistance to viral infection, and this resistance is accompanied by increases in IFN‐I production and IRF7 stability. Mechanistically, we find that the XAF1‐XIAP axis controls the activity of KLHL22, an adaptor of the BTB‐CUL3‐RBX1 E3 ligase complex through a ubiquitin‐dependent pathway. CUL3‐KLHL22 directly targets IRF7 and catalyzes its K48‐linked ubiquitination and proteasomal degradation. These findings reveal unexpected functions of the XAF1‐XIAP axis and KLHL22 in the regulation of IRF7 stability and highlight an important target for antiviral innate immunity.