Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan.
Research Center for Advanced Immunology, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan.
Int Immunol. 2020 Jan 9;32(1):5-15. doi: 10.1093/intimm/dxz067.
Dedicator of cytokinesis (DOCK) proteins constitute a family of evolutionarily conserved guanine nucleotide exchange factors (GEFs) for the Rho family of GTPases. Although DOCK family proteins do not contain the Dbl homology domain typically found in other GEFs, they mediate the GTP-GDP exchange reaction through the DOCK homology region-2 (DHR-2) domain. In mammals, this family consists of 11 members, each of which has unique functions depending on the expression pattern and the substrate specificity. For example, DOCK2 is a Rac activator critical for migration and activation of leukocytes, whereas DOCK8 is a Cdc42-specific GEF that regulates interstitial migration of dendritic cells. Identification of DOCK2 and DOCK8 as causative genes for severe combined immunodeficiency syndromes in humans has highlighted their roles in immune surveillance. In addition, the recent discovery of a naturally occurring DOCK2-inhibitory metabolite has uncovered an unexpected mechanism of tissue-specific immune evasion. On the other hand, GEF-independent functions have been shown for DOCK8 in antigen-induced IL-31 production in helper T cells. This review summarizes multifaced functions of DOCK family proteins in the immune system.
细胞分裂的配体（DOCK）蛋白构成了一个进化上保守的 Rho 家族 GTP 酶的鸟嘌呤核苷酸交换因子（GEF）家族。尽管 DOCK 家族蛋白不含有通常在其他 GEF 中发现的 Dbl 同源结构域，但它们通过 DOCK 同源结构域-2（DHR-2）结构域介导 GTP-GDP 交换反应。在哺乳动物中，该家族由 11 个成员组成，每个成员根据表达模式和底物特异性具有独特的功能。例如，DOCK2 是一种 Rac 激活剂，对于白细胞的迁移和激活至关重要，而 DOCK8 是一种 Cdc42 特异性 GEF，调节树突状细胞的间质迁移。DOCK2 和 DOCK8 作为人类严重联合免疫缺陷综合征的致病基因的鉴定突出了它们在免疫监视中的作用。此外，最近发现了一种天然存在的 DOCK2 抑制代谢物，揭示了组织特异性免疫逃避的一种意外机制。另一方面，在辅助性 T 细胞中，DOCK8 已经显示出抗原诱导的 IL-31 产生的 GEF 独立功能。本综述总结了 DOCK 家族蛋白在免疫系统中的多方面功能。
