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

doi:10.1126/science.aay5663

GSTDTAP > 气候变化

DOI	10.1126/science.aay5663
	HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease
	Sarah A. Cook; William A. Comrie; M. Cecilia Poli; Morgan Similuk; Andrew J. Oler; Aiman J. Faruqi; Douglas B. Kuhns; Sheng Yang; Alexander Vargas-Hernández; Alexandre F. Carisey; Benjamin Fournier; D. Eric Anderson; Susan Price; Margery Smelkinson; Wadih Abou Chahla; Lisa R. Forbes; Emily M. Mace; Tram N. Cao; Zeynep H. Coban-Akdemir; Shalini N. Jhangiani; Donna M. Muzny; Richard A. Gibbs; James R. Lupski; Jordan S. Orange; Geoffrey D. E. Cuvelier; Moza Al Hassani; Nawal Al Kaabi; Zain Al Yafei; Soma Jyonouchi; Nikita Raje; Jason W. Caldwell; Yanping Huang; Janis K. Burkhardt; Sylvain Latour; Baoyu Chen; Gehad ElGhazali; V. Koneti Rao; Ivan K. Chinn; Michael J. Lenardo
	2020-07-10
发表期刊	Science
出版年	2020
英文摘要	The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook et al. studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies. Science , this issue p. [202][1] 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. [1]: /lookup/doi/10.1126/science.aay5663
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/283404
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Sarah A. Cook,William A. Comrie,M. Cecilia Poli,et al. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease[J]. Science,2020.
APA	Sarah A. Cook.,William A. Comrie.,M. Cecilia Poli.,Morgan Similuk.,Andrew J. Oler.,...&Michael J. Lenardo.(2020).HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.Science.
MLA	Sarah A. Cook,et al."HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease".Science (2020).