| First Author | Wei J | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 49 | Pages | 13000-13005 |
| PubMed ID | 29180417 | Mgi Jnum | J:254306 |
| Mgi Id | MGI:6103525 | Doi | 10.1073/pnas.1713462114 |
| Citation | Wei J, et al. (2017) SNX8 mediates IFNgamma-triggered noncanonical signaling pathway and host defense against Listeria monocytogenes. Proc Natl Acad Sci U S A 114(49):13000-13005 |
| abstractText | IFNgamma is a cytokine that plays a key role in host defense against intracellular pathogens. In addition to the canonical JAK-STAT1 pathway, IFNgamma also activates an IKKbeta-mediated noncanonical signaling pathway that is essential for induction of a subset of downstream effector genes. The molecular mechanisms and functional significance of this IFNgamma-triggered noncanonical pathway remains enigmatic. Here, we identified sorting nexin 8 (SNX8) as an important component of the IFNgamma-triggered noncanonical signaling pathway. SNX8-deficiency impaired IFNgamma-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 IKKbeta and promoted their association. IFNgamma induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKbeta to the JAK1 complex. SNX8-deficiency impaired IFNgamma-induced oligomerization and autophosphorylation of IKKbeta at Ser177, which is critical for selective induction of downstream genes. Our findings suggest that SNX8 acts as a link for IFNgamma-triggered noncanonical signaling pathway, which induces a subset of downstream genes important for host defense against L. monocytogenes infection. |
