SNX8 mediates IFNγ-triggered noncanonical signaling pathway and host defense against Listeria monocytogenes

IFNγ is a cytokine that induces various downstream genes for host defense against pathogens. How IFNγ induces downstream genes via the classical JAK1-STAT1 pathway is well understood, but how IFNγ induces a subset of downstream genes via the kinase IKKβ remains enigmatic. We identified SNX8 protein as an important component of this IFNγ-triggered noncanonical pathway. SNX8 deficiency impairs IFNγ-triggered induction of a subset of downstream genes, rendering the mouse more susceptible to infection of intracellular bacteria Listeria monocytogenes. Mechanistically, IFNγ induces phosphorylation of SNX8, which promotes the recruitment of IKKβ to the JAK1 complex and subsequent activation of IKKβ. Our findings suggest that SNX8 acts as a link for IFNγ-triggered noncanonical signaling pathway and host defense against intracellular bacteria infection.