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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

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SNX8 mediates IFNγ-triggered noncanonical signaling pathway and host defense against <i>Listeria monocytogenes</i>.

Wei Jin J Guo Wei W Lian Huan H Yang Qing Q Lin Heng H Li Shu S Shu Hong-Bing HB

Proceedings of the National Academy of Sciences of the United States of America 20171127 49

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 ...[more]

PMID: 29180417

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Project description:Intrauterine Listeria monocytogenes (L. monocytogenes) infections pose a major threat during pregnancy via affecting placental immune responses. However, the underlying mechanisms of placental defense against this pathogen remain ill-defined. Therefore, this study aims to investigate the function and the mechanism of inflammasomes on against L. monocytogenes infection during pregnancy. A listeriosis murine model and cell culture system was used to investigate the role of trophoblastic nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) in orchestrating innate immune responses to L. monocytogenes infection. Caspase-1 activity was determined using a caspase-1 activity colorimetric kit. NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) in placental tissue was detected by immunohistochemistry. NLRP3 in HTR-8/SVneo cells was also detected by immunofluorescence. The expression of interleukin 1β (IL-1β), NLRP3, ASC, and caspase-1 was detected by Western blot. We characterized the NLRP3 inflammasome in trophoblast cells according to whether L. monocytogenes infection increased the activation of caspase-1 and the release of IL-1β. For human or mouse IL-1β in the culture supernatants and mouse tissue lysates were analyzed using ELISA Kits. Trophoblast cells constitutively expressed the components of the NLRP3 inflammasome. In vitro, L. monocytogenes triggers NLRP3 inflammasome activation in trophoblast cells by inducing caspase-1 activation, increasing the NLRP3 protein levels, IL-1β maturation and secretion in HTR-8/SVneo cells. In vivo, L. monocytogenes induces fetal resorption and IL-1β processing in pregnant mice. In addition, NLRP3-deficient mice were more prone to fetal loss than their wild-type counterparts following infection with L. monocytogenes at a lower infective dose. We conclude that trophoblast cells respond to L. monocytogenes infection through the NLRP3 receptor, resulting in inflammasome activation and IL-1β production, which prevents listeriosis during pregnancy.

Dataset Information

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

Publications

SNX8 mediates IFNγ-triggered noncanonical signaling pathway and host defense against <i>Listeria monocytogenes</i>.

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