Tiam1/Rac1 complex controls Il17a transcription and autoimmunity

Ahmed T. Kurdi, Ribal Bassil, Marta Olah, Chuan Wu, Sheng Xiao, Mariko Taga, Michael Frangieh, Thomas Buttrick, William Orent, Elizabeth M. Bradshaw, Samia J. Khoury () and Wassim Elyaman ()
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Ahmed T. Kurdi: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School
Ribal Bassil: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School
Marta Olah: Program in Translational NeuroPsychiatric Genomics, Brigham and Women’s Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT
Chuan Wu: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School
Sheng Xiao: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School
Mariko Taga: Program in Translational NeuroPsychiatric Genomics, Brigham and Women’s Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT
Michael Frangieh: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School
Thomas Buttrick: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School
William Orent: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School
Elizabeth M. Bradshaw: Program in Translational NeuroPsychiatric Genomics, Brigham and Women’s Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT
Samia J. Khoury: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School
Wassim Elyaman: Program in Translational NeuroPsychiatric Genomics, Brigham and Women’s Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract RORγt is a master transcription factor of Th17 cells and considered as a promising drug target for the treatment of autoimmune diseases. Here, we show the guanine nucleotide exchange factor, Tiam1, and its cognate Rho-family G protein, Rac1, regulate interleukin (IL)17A transcription and autoimmunity. Whereas Tiam1 genetic deficiency weakens IL-17A expression partially and inhibits the development of experimental autoimmune encephalomyelitis (EAE), deletion of Rac1 in T cells exhibits more robust effects on Th17 cells and EAE. We demonstrate Tiam1 and Rac1 form a complex with RORγt in the nuclear compartment of Th17 cells, and together bind and activate the Il17 promoter. The clinical relevance of these findings is emphasized by pharmacological targeting of Rac1 that suppresses both murine and human Th17 cells as well as EAE. Thus, our findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis.

Date: 2016
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DOI: 10.1038/ncomms13048

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