Wang et al. identify MARK2 as a key regulator of innate antiviral immunity. The phosphorylation of GEF-H1 at Ser645 by MARK2 enhances TBK1 activation and induces IFN-β and interferon-stimulated genes. This establishes the MARK2–GEF-H1–TBK1 axis as a fundamental component of host antiviral defense.