MARK2 serves as a key regulator of host antiviral immunity through GEF-H1 phosphorylation

The innate immune system detects viral infections and mounts robust type I interferon (IFN-I) responses to establish antiviral defenses. However, the regulatory mechanisms that control the amplitude and duration of IFN-I signaling remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2)-a serine/threonine kinase of the AMPK family traditionally known for its roles in cell polarity and microtubule dynamics-as a regulator of antiviral immunity. MARK2 interacts with guanine nucleotide exchange factor H1 (GEF-H1) and phosphorylates it at Ser645 in a microtubule-dependent manner. Phosphorylated GEF-H1 then enhances TBK1 activation, thereby promoting strong induction of IFN-I and IFN-stimulated genes (ISGs). Furthermore, MARK2 drives transcriptional upregulation of GEF-H1 itself as an ISG, establishing a positive feedback loop that sustains antiviral signaling. Together, these findings identify MARK2 as an antiviral signaling kinase that amplifies innate immune responses through GEF-H1 phosphorylation, offering mechanistic insights into the regulation of innate antiviral immunity.