page_title: SNX8
section_title: IFNγ-triggered IKKβ-mediated noncanonical signaling pathway
hierarchical_section_title: SNX8 / Biological functions and its molecular mechanisms / Innate immune response / IFNγ-triggered IKKβ-mediated noncanonical signaling pathway
context_page_description: The SNX8 is a sorting nexin protein involved in intracelullar molecular traffic from the early endosomes to the TGN. It is suggested that it acts as an adaptor protein in events related to immune response and cholesterol regulation, for example. As a protein of the SNXs family, the SNX8 is formed of 465 aminoacids and presents a BAR-domain and a PX-domain which are very relevant in relation to its functions. Furthermore, SNX8 study is motivated by its medical significance in relation to diseases such as Alzheimer's Disease, cancer, neurodevelopmental malformations and to its role in fighting against viral infections.
context_section_description: SNX8 is a component of an IKKβ-mediated noncanonical signaling pathway triggered by the interferon gamma, which takes places parallelly to the more known IFNγ-induced JAK-STAT1 mediated pathway. Overall, it participates in a series of chemical reactions and molecular interactions that lead to the selective promotion of a particular subset of downstream effector gene transcription that encode IFNγ-induced GTPases of the GBP family, which participate in host defense against intracellular pathogens, and secretion proteins of the chemokine family such as CXCL9, CXCL10, and CXCL11 which  present direct antimicrobial activity. In addition, SNX8 enhances the IFNγ-induced activation of the IRF1 promoter in a dose-dependent manner.
  Specifically, the steps of this pathway that are regulated by SNX8 are the following. The reception of IFNγ activates Janus kinase 1, resulting in the stimulation of its association with Sxn8 above standard constitutive levels. The link between these two protein within the JAK1-SNX8 complex allows JAK1 to catalyse SNX8's tyrosines phosphorylation in positions 95 and 126. This phosphorylation activates the JAK1-SNX, and the SNX8 acts as an adaptor or scaffolding protein by permitting the recruitment of the inhibitor of nuclear factor-kappa-B kinase subunit beta (IKKβ) to JAK1 in the JAK1-SNX8-IKKβ complex. This linkage is essential for IKKβ activation through autophosphorylation at serine in position 177 (as SNX8 lacks enzymatic activity) and further dimerization and oligomerization.
caption: Simplified scheme of SNX8 participation in the IFNγ-triggered IKKβ-mediated noncanonical signaling pathway (autophosphorylation not shown).[5]
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