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
Date Published2020 Jul 10
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

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.

Alternate JournalScience
PubMed ID32647003
PubMed Central IDPMC8383235
Grant ListR01 AI120989 / AI / NIAID NIH HHS / United States
Z01 AI000566 / ImNIH / Intramural NIH HHS / United States
R01 AI065644 / AI / NIAID NIH HHS / United States
R35 GM128786 / GM / NIGMS NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R01 AI067946 / AI / NIAID NIH HHS / United States
FI2 GM119979 / GM / NIGMS NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States

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