Hippo kinase NDR1 crosstalks with GSK3 and positively regulates type I interferon-mediated antiviral innate immunity

Type I interferons (IFN-Is) are central mediators of antiviral innate immunity, yet the molecular pathways that fine-tune their rapid induction remain incompletely defined. Here, we identified the Hippo pathway kinase NDR1 as a key positive regulator of IFN-β-mediated antiviral responses. NDR1 forms a constitutive complex with GSK3 and selectively blocks its interaction with Akt, thereby preventing Akt-dependent inhibitory phosphorylation of GSK3 at Ser21/9 and maintaining GSK3 activity. Sustained GSK3 function enables efficient STAT1 activation, a central event required for both the initiation and amplification of IFN-β production. Consequently, loss of NDR1 disrupts this regulatory module, leading to reduced STAT1 phosphorylation, diminished IFN-β expression, and increased viral replication in macrophages. These mechanistic defects are mirrored in vivo, as NDR1-deficient mice exhibit impaired systemic IFN-β responses and markedly heightened susceptibility to viral infection. Together, our findings establish a previously unappreciated NDR1-GSK3-STAT1 signalling axis that integrates Hippo pathway components into antiviral innate immunity and reveal NDR1 as a potential target for enhancing host resistance to viral pathogens.