DYRK1B: A Novel positive regulator of RIG-I in antiviral innate immunity.

Abstract

Among the intracellular sensors of innate immunity against infection, RIG-I-like receptors (RLRs) serve as cytosolic surveillance sensors that detect viral RNA species. However, the role of kinases in modulating RIG-I in a catalytically-independent manner is not well known. In this study, we report that protein kinase DYRK1B is a novel positive regulator of RIG-I-mediated antiviral innate immunity. Overexpression of DYRK1B markedly amplified RNA virus-induced IFN-I production, whereas CRISPR-mediated knockout of DYRK1B substantially attenuated these antiviral responses. Mechanistic investigation revealed that this regulatory role operates independently of DYRK1B's catalytic kinase function; instead, DYRK1B functions as an adaptor protein that connects TRIM25 with RIG-I, thereby promoting TRIM25-mediated K63-linked polyubiquitination of RIG-I, an essential modification required for RIG-I functional activation. Collectively, our findings reveal that DYRK1B enhances innate immunity against RNA viruses by strengthening the physical association of RIG-I with TRIM25, providing a more profound understanding of the mechanisms involved in antiviral immune regulation.