CREB/CRTC2-Induced GPR65 Orchestrates Th17 Metabolic Fitness and Pathogenic Effector Function

Cave, S.; Patel, D.; Yang, Q.; Liang, Y.; Swanson, J. H.; Versage, K.; Chikezie, I.; Carra Hernandez, J.; Ybanez, C. M.; Yang, L. V.; Zheng, Y.; Hernandez, J.

doi:10.64898/2026.03.27.714848

bioRxiv · 10.64898/2026.03.27.714848

CREB/CRTC2-Induced GPR65 Orchestrates Th17 Metabolic Fitness and Pathogenic Effector Function

Cave, S.·Patel, D.·Yang, Q.·Liang, Y.·Swanson, J. H.·Versage, K.·Chikezie, I.·Carra Hernandez, J.·Ybanez, C. M.·Yang, L. V.·Zheng, Y.·Hernandez, J.

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Abstract

GPR65 has been shown to be a critical regulator of Th17 cell pathogenicity. Loss of GPR65 in mice results in a decrease in Th17 cells and reduced susceptibility to a mouse model of multiple sclerosis. The CREB/CRTC2 pathway has emerged as an important regulator of immune function. We have previously shown that the CREB/CRTC2 pathway modulates autoimmune disease by promoting differentiation of Th17 cells. In this study we performed RNA-seq to identify Th17 genes regulated by the CREB/CRTC2 pathway. Our RNA-seq analysis led us to uncover the first mechanism of regulation of the orphan receptor GPR65 by the CREB/CRTC2 pathway. We show that GPR65 is a target of the CREB/CRTC2 pathway through expression studies and chromatin immunoprecipitation. In addition, we show that targeting GPR65 with small molecules alters the expression of IL-17A. Understanding the regulation of GPR65 will be crucial in developing small molecules to treat patients with Th17 cell-mediated disorders.

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Cave, S., Patel, D., Yang, Q., Liang, Y., Swanson, J. H., Versage, K., Chikezie, I., Carra Hernandez, J., Ybanez, C. M., Yang, L. V., Zheng, Y., Hernandez, J.. 2026-03-30. CREB/CRTC2-Induced GPR65 Orchestrates Th17 Metabolic Fitness and Pathogenic Effector Function. https://doi.org/10.64898/2026.03.27.714848

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