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

IFN gamma is a cytokine that plays a key role in host defense against intracellular pathogens. In addition to the canonical JAK-STAT1 pathway, IFN gamma also activates an IKK beta-mediated noncanonical signaling pathway that is essential for induction of a subset of downstream effector genes. The molecular mechanisms and functional significance of this IFN gamma-triggered noncanonical pathway remains enigmatic. Here, we identified sorting nexin 8 (SNX8) as an important component of the IFN gamma-triggered noncanonical signaling pathway. SNX8-deficiency impaired IFN gamma-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 interactedwith JAK1 and IKK beta and promoted their association. IFN gamma induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKK beta to the JAK1 complex. SNX8-deficiency impaired IFN gamma-induced oligomerization and autophosphorylation of IKK beta at Ser177, which is critical for selective induction of downstream genes. Our findings suggest that SNX8 acts as a link for IFN gamma-triggered noncanonical signaling pathway, which induces a subset of downstream genes important for host defense against L. monocytogenes infection.