HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.

TitleHEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsCook, SA, Comrie, WA, M Poli, C, Similuk, M, Oler, AJ, Faruqi, AJ, Kuhns, DB, Yang, S, Vargas-Hernandez, A, Carisey, AF, Fournier, B, D Anderson, E, Price, S, Smelkinson, M, Chahla, WAbou, Forbes, LR, Mace, EM, Cao, TN, Coban-Akdemir, ZH, Jhangiani, SN, Muzny, DM, Gibbs, RA, Lupski, JR, Orange, JS, Cuvelier, GDE, Hassani, MAl, Kaabi, NAl, Yafei, ZAl, Jyonouchi, S, Raje, N, Caldwell, JW, Huang, Y, Burkhardt, JK, Latour, S, Chen, B, ElGhazali, G, V Rao, K, Chinn, IK, Lenardo, MJ
JournalScience
Volume369
Issue6500
Pagination202-207
Date Published2020 07 10
ISSN1095-9203
KeywordsActins, ADP-Ribosylation Factor 1, CD4-Positive T-Lymphocytes, Cell Proliferation, Cytokines, Humans, Immunologic Deficiency Syndromes, Lymphoproliferative Disorders, Mechanistic Target of Rapamycin Complex 2, Membrane Proteins, Pedigree, Phosphorylation, Wiskott-Aldrich Syndrome Protein Family
Abstract

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in , which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.

DOI10.1126/science.aay5663
Alternate JournalScience
PubMed ID32647003
Grant ListR01 AI120989 / AI / NIAID NIH HHS / United States
R35 GM128786 / GM / NIGMS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States