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

Significance 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. IFNγ is a cytokine that plays a key role in host defense against intracellular pathogens. In addition to the canonical JAK-STAT1 pathway, IFNγ also activates an IKKβ-mediated noncanonical signaling pathway that is essential for induction of a subset of downstream effector genes. The molecular mechanisms and functional significance of this IFNγ-triggered noncanonical pathway remains enigmatic. Here, we identified sorting nexin 8 (SNX8) as an important component of the IFNγ-triggered noncanonical signaling pathway. SNX8-deficiency impaired IFNγ-triggered induction of a subset of downstream genes. Snx8−/− mice infected with Listeria monocytogenes exhibited lower serum cytokine levels and higher bacterial loads in the livers and spleens, resulting in higher lethality. Mechanistically, SNX8 interacted with JAK1 and IKKβ and promoted their association. IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKβ to the JAK1 complex. SNX8-deficiency impaired IFNγ-induced oligomerization and autophosphorylation of IKKβ at Ser177, which is critical for selective induction of downstream genes. Our findings suggest that SNX8 acts as a link for IFNγ-triggered noncanonical signaling pathway, which induces a subset of downstream genes important for host defense against L. monocytogenes infection.