A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals
A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals
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DOI：
10.1126/scisignal.aac9171
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发表时间：
2016-03-22
影响因子：
7.3
通讯作者：
Gwack, Yousang
中科院分区：
文献类型：
--
作者：
Srikanth, Sonal;Kim, Kyun-Do;Gwack, Yousang
鸟苷三磷酸酶（GTPases）在人类基因组中存在60多个Rab家族成员。Rab gtp酶是一种小蛋白质，主要参与囊泡的形成、运输和融合。我们发现，CRACR2A （Ca2+释放激活的Ca2+通道调节剂2A）编码一个淋巴细胞特异性的大型Rab GTPase，该酶包含多个功能域，包括eff -hand基元，脯氨酸丰富域（PRD）和Rab GTPase结构域，该结构域具有非常规的烯酰化位点。通过在细胞和敲除小鼠中进行基因沉默实验，我们证明了CRACR2A在响应T细胞受体（TCR）刺激时激活Ca2+和c-Jun n末端激酶信号通路中的作用。含有这种Rab GTPase的囊泡从高尔基体附近转移到T细胞和同源抗原呈递细胞之间形成的免疫突触，以激活这些信号通路。CRACR2A的PRD与胍核苷酸交换因子Vav1之间的相互作用是这些囊泡在免疫突触积聚的必要条件。此外，我们证明了GTP结合和丙烯酰化与CRACR2A在高尔基体附近的定位及其稳定性有关。我们的研究结果揭示了一个以前未被表征的大Rab GTPase和高尔基体附近的囊泡在TCR信号传导中的功能。具有类似结构域结构的其他gtpase可能在T细胞中具有类似的功能。
More than 60 members of the Rab family of guanosine triphosphatases (GTPases) exist in the human genome. Rab GTPases are small proteins that are primarily involved in the formation, trafficking, and fusion of vesicles. We showed that CRACR2A (Ca2+ release-activated Ca2+ channel regulator 2A) encodes a lymphocyte-specific large Rab GTPase that contains multiple functional domains, including EF-hand motifs, a proline-rich domain (PRD), and a Rab GTPase domain with an unconventional prenylation site. Through experiments involving gene silencing in cells and knockout mice, we demonstrated a role for CRACR2A in the activation of the Ca2+ and c-Jun N-terminal kinase signaling pathways in response to T cell receptor (TCR) stimulation. Vesicles containing this Rab GTPase translocated from near the Golgi to the immunological synapse formed between a T cell and a cognate antigen-presenting cell to activate these signaling pathways. The interaction between the PRD of CRACR2A and the guanidine nucleotide exchange factor Vav1 was required for the accumulation of these vesicles at the immunological synapse. Furthermore, we demonstrated that GTP binding and prenylation of CRACR2A were associated with its localization near the Golgi and its stability. Our findings reveal a previously uncharacterized function of a large Rab GTPase and vesicles near the Golgi in TCR signaling. Other GTPases with similar domain architectures may have similar functions in T cells.