UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6

Abstract

Key Points UBL4A is a novel IFN-stimulated gene. UBL4A positively regulates innate immune response. UBL4A interacts with and targets TRAF6 for K63-linked ubiquitination. Human UBL4A/GdX, encoding an ubiquitin-like protein, was shown in this study to be upregulated by viral infection and IFN stimulation. Then the functions of UBL4A in antiviral immune response were characterized. Overexpression of UBL4A promoted RNA virus–induced ISRE or IFN-β or NF-κB activation, leading to enhanced type I IFN transcription and reduced virus replication. Consistently, knockdown of UBL4A resulted in reduced type I IFN transcription and enhanced virus replication. Additionally, overexpression of UBL4A promoted virus-induced phosphorylation of TBK1, IRF3, and IKKα/β. Knockdown of UBL4A inhibited virus-induced phosphorylation of TBK1, IRF3, and IKKα/β. Coimmunoprecipitation showed that UBL4A interacted with TRAF6, and this interaction was enhanced upon viral infection. Ubiquitination assays showed that UBL4A promoted the K63-linked ubiquitination of TRAF6. Therefore, we reveal a novel positive feedback regulation of UBL4A in innate immune response combating virus invasion by enhancing the K63-linked ubiquitination of TRAF6.