Rab GTPases in antiviral innate immunity: mechanisms and potential therapeutics.

Abstract

Antiviral innate immunity provides the first line of host defense against viral infection by sensing viral components and rapidly activating type I interferon (IFN) programs that restrict viral replication and spread. The initiation, spatial organization, and termination of these responses depend on tightly regulated intracellular membrane trafficking, positioning Rab GTPases as key coordinators of antiviral immune signaling. Rab GTPases are small molecular switches that regulate vesicle identity, cargo transport, organelle maturation, and signal termination. Beyond their established roles in viral entry, genome transport, assembly, and egress, Rab proteins organize signaling by Toll-like receptors (TLR), retinoic acid-inducible gene I-like receptors, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, and type I IFN receptors. Rab11A and Rab8A regulate TLRs trafficking, Rab1B supports formation of a complex between mitochondrial antiviral-signaling protein and tumor necrosis factor receptor-associated factor 3, Rab2B promotes cGAS-STING activation, and Rab7A controls endolysosomal trafficking and signal termination. Viruses can subvert these protective functions by altering Rab localization, activation, or effector interactions to promote replication and immune evasion. This review summarizes these bidirectional Rab GTPase checkpoints and discusses therapeutic strategies targeting virus-Rab interfaces, Rab regulators, and protective lysosomal functions while minimizing disruption of essential membrane trafficking.