气候变化领域集成服务门户(CCPortal): HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease

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DOI	10.1126/science.aay5663
	HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease
	Cook S.A.; Comrie W.A.; Poli M.C.; Similuk M.; Oler A.J.; Faruqi A.J.; Kuhns D.B.; Yang S.; Vargas-Hernández A.; Carisey A.F.; Fournier B.; Anderson D.E.; Price S.; Smelkinson M.; Abou Chahla W.; Forbes L.R.; Mace E.M.; Cao T.N.; Coban-Akdemir Z.H.; Jhangiani S.N.; Muzny D.M.; Gibbs R.A.; Lupski J.R.; Orange J.S.; Cuvelier G.D.E.; Al Hassani M.; Al Kaabi N.; Al Yafei Z.; Jyonouchi S.; Raje N.; Caldwell J.W.; Huang Y.; Burkhardt J.K.; Latour S.; Chen B.; ElGhazali G.; Rao V.K.; Chinn I.K.; Lenardo M.J.
发表日期	2020
ISSN	10959203
起始页码	202
结束页码	207
卷号	369 期号:6500
英文摘要	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 NCKAP1L, 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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
关键词	actin adenosine diphosphate ribosylation factor 1 ARF1 protein, human cytokine mammalian target of rapamycin complex 2 membrane protein NCKAP1L protein, human WASF1 protein, human WASF2 protein, human WASF3 protein, human Wiskott Aldrich syndrome protein biosynthesis CD4+ T lymphocyte cell proliferation chemistry genetics human immune deficiency immunology lymphoproliferative disease metabolism pedigree phosphorylation physiology Actins 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
语种	英语
来源机构	Science (New York, N.Y.)
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/133356
推荐引用方式 GB/T 7714	Cook S.A.,Comrie W.A.,Poli M.C.,et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease[J]. Science (New York, N.Y.),2020,369(6500).
APA	Cook S.A..,Comrie W.A..,Poli M.C..,Similuk M..,Oler A.J..,...&Lenardo M.J..(2020).HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.,369(6500).
MLA	Cook S.A.,et al."HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease".369.6500(2020).