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RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development

机译:RhoH GTPase募集并激活T细胞受体信号传导和胸腺细胞发育所需的Zap70

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摘要

RhoH is a hematopoietic-specific, GTPase-deficient member of the Rho GTPase family with unknown physiological function. Here we demonstrate that Rhoh(-/-) mice have impaired T cell receptor ( TCR)-mediated thymocyte selection and maturation, resulting in T cell deficiency. RhoH deficiency resulted in defective CD3 zeta phosphorylation, impaired translocation of the signaling molecule Zap70 to the immunological synapse and reduced activation of Zap70-mediated signaling in thymic and peripheral T cells. Proteomic analyses demonstrated that RhoH is a component of TCR signaling and is required for recruitment of Zap70 to the TCR through interaction with RhoH noncanonical immunoreceptor tyrosine-based activation motifs ( ITAMs). In vivo reconstitution studies also demonstrated that RhoH function depends on phosphorylation of the RhoH ITAMs. These findings suggest that RhoH is a critical regulator of thymocyte development and TCR signaling by mediating recruitment and activation of Zap70.
机译:RhoH是Rho GTPase家族的造血特异性GTPase缺陷型成员,具有未知的生理功能。在这里,我们证明Rhoh(-/-)小鼠受损的T细胞受体(TCR)介导的胸腺细胞选择和成熟,从而导致T细胞缺乏。 RhoH缺乏导致CD3 zeta磷酸化缺陷,信号分子Zap70向免疫突触的易位受损以及胸腺和外周T细胞中Zap70介导的信号传导的激活减少。蛋白质组学分析表明RhoH是TCR信号的一个组成部分,并且是通过与RhoH非经典免疫受体酪氨酸基激活基序(ITAM)相互作用将Zap70募集到TCR所必需的。体内重构研究还表明,RhoH功能取决于RhoH ITAM的磷酸化。这些发现表明,RhoH通过介导Zap70的募集和激活是胸腺细胞发育和TCR信号传导的关键调节剂。

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