Zhang Huiling, Guo Zhihan, Yi Jingjing, Wu Jiaying, Wang Yihan, Ren Tingrong, Zhang Yuqi, Zhao Haiping, Wu Nana, Wei Gaigai, Zhang Duanwu
Children's Hospital of Fudan University, National Children's Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Children's Hospital of Fudan University, National Children's Medical Center, Fudan University, Shanghai, China.
Cell Death Differ. 2025 May 22. doi: 10.1038/s41418-025-01529-0.
T cells are central to adaptive immunity, with proper thymic development and egress critical for T cell homeostasis in peripheral tissues. The molecular mechanisms governing thymic egress remain poorly understood. Here, we identify Rho GTPase-activating protein 30 (ARHGAP30), predominantly expressed in lymphoid organs and previously uncharacterized in immunity, as a key regulator of thymocyte migration and egress. Loss of ARHGAP30 leads to impaired thymic development and severe T cell lymphopenia. Notably, Arhgap30-deficient mice exhibit a reduced number of immature single-positive (SP) thymocytes but a normal number of mature SP thymocytes, indicating a blockade in thymic egress. Mechanistically, ARHGAP30 deficiency lowers GTP-bound active RAC1 independent of its GAP activity, impairing actin polarization and thymocyte motility. ARHGAP30 selectively binds and stabilizes active RAC1, preventing its proteasomal degradation via K48-linked ubiquitination. These findings establish ARHGAP30 as a critical checkpoint for thymic egress and underscore its essential role in maintaining peripheral T cell homeostasis.
T细胞对于适应性免疫至关重要，胸腺的正常发育和输出对于外周组织中T细胞的稳态至关重要。目前，关于胸腺输出的分子机制仍知之甚少。在此，我们鉴定出Rho GTP酶激活蛋白30（ARHGAP30），其主要在淋巴器官中表达，且此前在免疫领域未被描述，它是胸腺细胞迁移和输出的关键调节因子。ARHGAP30的缺失会导致胸腺发育受损和严重的T细胞淋巴细胞减少。值得注意的是，Arhgap30基因缺陷小鼠的未成熟单阳性（SP）胸腺细胞数量减少，但成熟SP胸腺细胞数量正常，这表明胸腺输出受阻。从机制上讲，ARHGAP30缺陷会降低与GTP结合的活性RAC1，而不依赖于其GAP活性，从而损害肌动蛋白极化和胸腺细胞运动。ARHGAP30选择性地结合并稳定活性RAC1，通过K48连接的泛素化防止其被蛋白酶体降解。这些发现确立了ARHGAP30作为胸腺输出的关键检查点，并强调了其在维持外周T细胞稳态中的重要作用。
