| First Author | Chuang HC | Year | 2018 |
| Journal | Sci Adv | Volume | 4 |
| Issue | 9 | Pages | eaat5401 |
| PubMed ID | 30214937 | Mgi Jnum | J:288082 |
| Mgi Id | MGI:6415911 | Doi | 10.1126/sciadv.aat5401 |
| Citation | Chuang HC, et al. (2018) GLK-IKKbeta signaling induces dimerization and translocation of the AhR-RORgammat complex in IL-17A induction and autoimmune disease. Sci Adv 4(9):eaat5401 |
| abstractText | Retinoic-acid-receptor-related orphan nuclear receptor gammat (RORgammat) 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)-RORgammat 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 Ctheta (PKCtheta) phosphorylated AhR at Ser(36) and induced AhR nuclear translocation. AhR also interacted with RORgammat and transported RORgammat into the nucleus. IKKbeta (inhibitor of nuclear factor kappaB kinase beta)-mediated RORgammat Ser(489) phosphorylation induced the AhR-RORgammat interaction. T cell receptor (TCR) signaling also induced the novel RORgammat phosphorylation and subsequent AhR-RORgammat interaction. Collectively, TCR signaling or GLK overexpression induces IL-17A transcription through the IKKbeta-mediated RORgammat phosphorylation and the AhR-RORgammat interaction in T cells. Our findings suggest that inhibitors of GLK or the AhR-RORgammat complex could be used as IL-17A-blocking agents for IL-17A-mediated autoimmune diseases. |
