SNX8 mediates IFN?-triggered noncanonical signaling pathway and host defense against Listeria monocytogenes.

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

SUBMITTER: Wei J 

PROVIDER: S-EPMC5724276 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature