GLK-IKK? signaling induces dimerization and translocation of the AhR-ROR?t complex in IL-17A induction and autoimmune disease.

ABSTRACT: Retinoic-acid-receptor-related orphan nuclear receptor ?t (ROR?t) controls the transcription of interleukin-17A (IL-17A), which plays critical roles in the pathogenesis of autoimmune diseases. Severity of several human autoimmune diseases is correlated with frequencies of germinal center kinase-like kinase (GLK) (also known as MAP4K3)-overexpressing T cells; however, the mechanism of GLK overexpression-induced autoimmunity remains unclear. We report the signal transduction converging on aryl hydrocarbon receptor (AhR)-ROR?t interaction to activate transcription of the IL-17A gene in T cells. T cell-specific GLK transgenic mice spontaneously developed autoimmune diseases with selective induction of IL-17A in T cells. In GLK transgenic T cells, protein kinase C? (PKC?) phosphorylated AhR at Ser³⁶ and induced AhR nuclear translocation. AhR also interacted with ROR?t and transported ROR?t into the nucleus. IKK? (inhibitor of nuclear factor ?B kinase ?)-mediated ROR?t Ser⁴⁸⁹ phosphorylation induced the AhR-ROR?t interaction. T cell receptor (TCR) signaling also induced the novel ROR?t phosphorylation and subsequent AhR-ROR?t interaction. Collectively, TCR signaling or GLK overexpression induces IL-17A transcription through the IKK?-mediated ROR?t phosphorylation and the AhR-ROR?t interaction in T cells. Our findings suggest that inhibitors of GLK or the AhR-ROR?t complex could be used as IL-17A-blocking agents for IL-17A-mediated autoimmune diseases.

SUBMITTER: Chuang HC 

PROVIDER: S-EPMC6135549 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature