Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6−/− mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)–containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6−/− mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells.
GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans
Y. Yao, P. Du Jiang, B.N. Chao, D. Cagdas, A.J. McMichael, A.K. Simon, and M.J. Lenardo contributed equally to this paper.
Disclosures: The authors declare no competing financial interests.
- Award Id(s): 958,A12
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Yikun Yao, Ping Du Jiang, Brittany N. Chao, Deniz Cagdas, Satoshi Kubo, Arasu Balasubramaniyam, Yu Zhang, Bella Shadur, Adeeb NaserEddin, Les R. Folio, Benjamin Schwarz, Eric Bohrnsen, Lixin Zheng, Matthew Lynberg, Simone Gottlieb, Michael A. Leney-Greene, Ann Y. Park, Ilhan Tezcan, Ali Akdogan, Rahsan Gocmen, Sevgen Onder, Avi Rosenberg, Elizabeth J. Soilleux, Errin Johnson, Peter K. Jackson, Janos Demeter, Samuel D. Chauvin, Florian Paul, Matthias Selbach, Haydar Bulut, Menna R. Clatworthy, Zewen K. Tuong, Hanlin Zhang, Benjamin J. Stewart, Catharine M. Bosio, Polina Stepensky, Simon Clare, Sundar Ganesan, John C. Pascall, Oliver Daumke, Geoffrey W. Butcher, Andrew J. McMichael, Anna Katharina Simon, Michael J. Lenardo; GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans. J Exp Med 6 June 2022; 219 (6): e20201405. doi: https://doi.org/10.1084/jem.20201405
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