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一个保守的 PI(4,5)P2 结合域对于 DOCK8 的免疫调节功能至关重要。

A conserved PI(4,5)P2-binding domain is critical for immune regulatory function of DOCK8.

机构信息

Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.

出版信息

Life Sci Alliance. 2021 Feb 11;4(4). doi: 10.26508/lsa.202000873. Print 2021 Apr.

DOI:10.26508/lsa.202000873
PMID:33574036
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7893821/
Abstract

DOCK8 is a Cdc42-specific guanine-nucleotide exchange factor that is essential for development and functions of various subsets of leukocytes in innate and acquired immune responses. Although DOCK8 plays a critical role in spatial control of Cdc42 activity during interstitial leukocyte migration, the mechanism remains unclear. We show that the DOCK homology region (DHR)-1 domain of DOCK8 binds specifically to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and is required for its recruitment to the plasma membrane. Structural and biochemical analyses reveal that DOCK8 DHR-1 domain consists of a C2 domain-like core with loops creating the upper surface pocket, where three basic residues are located for stereospecific recognition of phosphoinositides. Substitution of the two basic residues, K576 and R581, with alanine abolished PI(4,5)P2 binding in vitro, ablated the ability of DOCK8 to activate Cdc42 and support leukocyte migration in three-dimensional collagen gels. Dendritic cells carrying the mutation exhibited defective interstitial migration in vivo. Thus, our study uncovers a critical role of DOCK8 in coupling PI(4,5)P2 signaling with Cdc42 activation for immune regulation.

摘要

DOCK8 是一种 Cdc42 特异性鸟嘌呤核苷酸交换因子，对于先天和获得性免疫反应中各种白细胞亚群的发育和功能至关重要。尽管 DOCK8 在间质白细胞迁移过程中 Cdc42 活性的空间控制中发挥着关键作用，但具体机制仍不清楚。我们发现 DOCK8 的 DOCK 同源区（DHR）-1 结构域特异性结合磷脂酰肌醇 4,5-二磷酸（PI（4,5）P2），并需要其募集到质膜。结构和生化分析表明，DOCK8 DHR-1 结构域由 C2 结构域样核心和形成上表面口袋的环组成，其中三个碱性残基用于对磷酸肌醇的立体特异性识别。用丙氨酸取代两个碱性残基 K576 和 R581，体外完全消除了 PI（4,5）P2 的结合，削弱了 DOCK8 激活 Cdc42 和支持三维胶原凝胶中白细胞迁移的能力。携带该突变的树突状细胞在体内表现出间质迁移缺陷。因此，我们的研究揭示了 DOCK8 在将 PI（4,5）P2 信号与 Cdc42 激活偶联以进行免疫调节中的关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/22b52214c286/LSA-2020-00873_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/05e93dff8daa/LSA-2020-00873_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/a0aea2d1aab7/LSA-2020-00873_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/abe2fc3badaf/LSA-2020-00873_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/f989ec380fd1/LSA-2020-00873_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/deb45d433df7/LSA-2020-00873_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/d121c0a7c661/LSA-2020-00873_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/5456eedeecfd/LSA-2020-00873_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/5951b8d8bc10/LSA-2020-00873_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/a442b1f06685/LSA-2020-00873_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/b19de116f44a/LSA-2020-00873_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/870608726292/LSA-2020-00873_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/df11e95bb3a3/LSA-2020-00873_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/22b52214c286/LSA-2020-00873_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/05e93dff8daa/LSA-2020-00873_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/a0aea2d1aab7/LSA-2020-00873_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/abe2fc3badaf/LSA-2020-00873_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/f989ec380fd1/LSA-2020-00873_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/deb45d433df7/LSA-2020-00873_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/d121c0a7c661/LSA-2020-00873_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/5456eedeecfd/LSA-2020-00873_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/5951b8d8bc10/LSA-2020-00873_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/a442b1f06685/LSA-2020-00873_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/b19de116f44a/LSA-2020-00873_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/870608726292/LSA-2020-00873_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/df11e95bb3a3/LSA-2020-00873_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b42d/7893821/22b52214c286/LSA-2020-00873_Fig7.jpg

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