美国国立卫生研究院Michael J. Lenardo研究团队发现，HEM1蛋白缺乏会破坏遗传性免疫失调患者体内mTORC2和F-肌动蛋白的调控。该研究于2020年7月10日发表于《科学》杂志。

研究人员探究了来自四个家族的五名患者，他们患有免疫缺陷性伴随先天性过敏、淋巴增生和细胞因子过量生产伴随NCKAP1L突变，其中NCKAP1L编码造血特异性HEM1蛋白。这些突变会导致HEM1蛋白和WAVE调节复合物（WRC）丢失或破坏与WRC调节剂Arf1的结合，从而损害肌动蛋白的聚合、突触形成和免疫细胞迁移。

WRC丢失引起的皮质肌动蛋白网络减少导致细胞因子释放失控和免疫反应过度。HEM1的丢失也阻止了雷帕霉素复合物2（mTORC2）依赖的AKT磷酸化、T细胞增殖和特定效应因子的功能，从而导致免疫缺陷。因此，进化上保守的HEM1蛋白同时调节丝状肌动蛋白（F-肌动蛋白）和mTORC2信号传导，以实现免疫反应中的平衡。

据悉，免疫缺陷常伴随机能亢进的免疫疾病。例如自身免疫、淋巴增生或先天性过敏，但这种偶然性在分子水平上的机制却很少被探究。

附：英文原文

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

Author: 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

Issue&Volume: 2020/07/10

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 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.

DOI: 10.1126/science.aay5663

Source: https://science.sciencemag.org/content/369/6500/202