Janssen Erin, Tohme Mira, Hedayat Mona, Leick Marion, Kumari Sudha, Ramesh Narayanaswamy, Massaad Michel J, Ullas Sumana, Azcutia Veronica, Goodnow Christopher C, Randall Katrina L, Qiao Qi, Wu Hao, Al-Herz Waleed, Cox Dianne, Hartwig John, Irvine Darrell J, Luscinskas Francis W, Geha Raif S
J Clin Invest. 2016 Oct 3;126(10):3837-3851. doi: 10.1172/JCI85774. Epub 2016 Sep 6.
Wiskott-Aldrich syndrome (WAS) is associated with mutations in the WAS protein (WASp), which plays a critical role in the initiation of T cell receptor-driven (TCR-driven) actin polymerization. The clinical phenotype of WAS includes susceptibility to infection, allergy, autoimmunity, and malignancy and overlaps with the symptoms of dedicator of cytokinesis 8 (DOCK8) deficiency, suggesting that the 2 syndromes share common pathogenic mechanisms. Here, we demonstrated that the WASp-interacting protein (WIP) bridges DOCK8 to WASp and actin in T cells. We determined that the guanine nucleotide exchange factor activity of DOCK8 is essential for the integrity of the subcortical actin cytoskeleton as well as for TCR-driven WASp activation, F-actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T cell transendothelial migration, and homing to lymph nodes, all of which also depend on WASp. These results indicate that DOCK8 and WASp are in the same signaling pathway that links TCRs to the actin cytoskeleton in TCR-driven actin assembly. Further, they provide an explanation for similarities in the clinical phenotypes of WAS and DOCK8 deficiency.
威斯科特-奥尔德里奇综合征（WAS）与WAS蛋白（WASp）的突变有关，WASp在T细胞受体驱动（TCR驱动）的肌动蛋白聚合起始过程中起关键作用。WAS的临床表型包括易感染、过敏、自身免疫和恶性肿瘤，且与胞质分裂专一蛋白8（DOCK8）缺陷的症状重叠，这表明这两种综合征具有共同的致病机制。在此，我们证明了WASp相互作用蛋白（WIP）在T细胞中将DOCK8与WASp和肌动蛋白连接起来。我们确定，DOCK8的鸟嘌呤核苷酸交换因子活性对于皮质下肌动蛋白细胞骨架的完整性以及TCR驱动的WASp激活、F-肌动蛋白组装、免疫突触形成、肌动蛋白灶形成、机械转导、T细胞跨内皮迁移和归巢至淋巴结至关重要，所有这些过程也都依赖于WASp。这些结果表明，在TCR驱动的肌动蛋白组装过程中，DOCK8和WASp处于将TCR与肌动蛋白细胞骨架连接起来的同一信号通路中。此外，它们为WAS和DOCK8缺陷临床表型的相似性提供了解释。
