Round June L, Tomassian Tamar, Zhang Min, Patel Viresh, Schoenberger Stephen P, Miceli M Carrie
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
J Exp Med. 2005 Feb 7;201(3):419-30. doi: 10.1084/jem.20041428.
Lipid raft membrane compartmentalization and membrane-associated guanylate kinase (MAGUK) family molecular scaffolds function in establishing cell polarity and organizing signal transducers within epithelial cell junctions and neuronal synapses. Here, we elucidate a role for the MAGUK protein, Dlgh1, in polarized T cell synapse assembly and T cell function. We find that Dlgh1 translocates to the immune synapse and lipid rafts in response to T cell receptor (TCR)/CD28 engagement and that LckSH3-mediated interactions with Dlgh1 control its membrane targeting. TCR/CD28 engagement induces the formation of endogenous Lck-Dlgh1-Zap70-Wiskott-Aldrich syndrome protein (WASp) complexes in which Dlgh1 acts to facilitate interactions of Lck with Zap70 and WASp. Using small interfering RNA and overexpression approaches, we show that Dlgh1 promotes antigen-induced actin polymerization, synaptic raft and TCR clustering, nuclear factor of activated T cell activity, and cytokine production. We propose that Dlgh1 coordinates TCR/CD28-induced actin-driven T cell synapse assembly, signal transduction, and effector function. These findings highlight common molecular strategies used to regulate cell polarity, synapse assembly, and transducer organization in diverse cellular systems.
脂筏膜区室化和膜相关鸟苷酸激酶（MAGUK）家族分子支架在建立细胞极性以及在上皮细胞连接和神经元突触中组织信号转导器方面发挥作用。在此，我们阐明了MAGUK蛋白Dlgh1在极化T细胞突触组装和T细胞功能中的作用。我们发现，响应T细胞受体（TCR）/CD28的结合，Dlgh1会转位至免疫突触和脂筏，并且LckSH3介导的与Dlgh1的相互作用控制其膜靶向。TCR/CD28的结合诱导内源性Lck-Dlgh1-Zap70-威斯科特-奥尔德里奇综合征蛋白（WASp）复合物的形成，其中Dlgh1起到促进Lck与Zap70和WASp相互作用的作用。使用小干扰RNA和过表达方法，我们表明Dlgh1促进抗原诱导的肌动蛋白聚合、突触筏和TCR聚集、活化T细胞核因子活性以及细胞因子产生。我们提出，Dlgh1协调TCR/CD28诱导的肌动蛋白驱动的T细胞突触组装、信号转导和效应器功能。这些发现突出了用于调节不同细胞系统中细胞极性、突触组装和转导器组织的常见分子策略。
