KAP1-Mediated Epigenetic Suppression in Anti-RNA Viral Responses by Direct Targeting RIG-I and MDA5

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I (encoded by Ddx58) and melanoma differentiation-associated gene 5 (MDA5) (encoded by Ifih1), are crucial for initiating antiviral responses. Endogenous retroviral elements (ERVs) are transposable elements derived from exogenous retroviruses that are integrated into the genome. KRAB-associated protein 1 (KAP1) is a key epigenetic suppressor of ERVs that protects cells from detrimental genome instability. Increased ERV transcripts are sensed by RLRs and trigger innate immune signaling. However, whether KAP1 directly controls RLRs activity remains unclear. In this study, we show that KAP1 attenuates RNA viral infection-induced type I IFNs and facilitates viral replication by inhibiting RIG-I/MDA5 expression in primary peritoneal macrophages (PMs) of C57BL/6J mice. Kap1 deficiency increases IFN-β expression and inhibits vesicular stomatitis virus replication in C57BL/6J mice in vivo. Mechanistically, KAP1 binds to the promoter regions of Ddx58 and Ifih1 and promotes the establishment of repressive histone marks in primary PMs of C57BL/6J mice. Concordantly, KAP1 suppresses the expression of RIG-I and MDA5 at the transcriptional level in primary PMs of C57BL/6J mice. Our results establish that KAP1 epigenetically suppresses host antiviral responses by directly targeting RIG-1 and MDA5, thus facilitating the immune escape of RNA viruses.