title: LRCH1 interferes with DOCK8-Cdc42-induced T cell migration and ameliorates experimental autoimmune encephalomyelitis.
abstract: Directional autoreactive CD4+T cell migration into the central nervous system plays a critical role in multiple sclerosis. Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation. Little is known about whether DOCK8 is related to multiple sclerosis (MS) and how to restrict its GEF activity. Using two screening systems, we found that LRCH1 competes with Cdc42 for interaction with DOCK8 and restrains T cell migration. In response to chemokine stimulation, PKCα phosphorylates DOCK8 at its three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration. Point mutations at the DOCK8 serine sites block chemokine- and PKCα-induced T cell migration. Importantly, Dock8 mutant mice or Lrch1 transgenic mice were protected from MOG (35-55) peptide-induced experimental autoimmune encephalomyelitis (EAE), whereas Lrch1-deficient mice displayed a more severe phenotype. Notably, DOCK8 expression was markedly increased in PBMCs from the acute phase of MS patients. Together, our study demonstrates LRCH1 as a novel effector to restrain PKCα-DOCK8-Cdc42 module-induced T cell migration and ameliorate EAE.
authors.affiliation: Key Laboratory of Systems Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Key Laboratory of Systems Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: HuaShan Hospital, Fudan University, Shanghai 200031, China.
authors.forename: Guixian
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Systems Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shengjie
authors.identifier: 0000-0001-9298-9124
authors.initials: S
authors.lastname: Xue
authors.affiliation: Key Laboratory of Systems Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yunzhen
authors.identifier: 0000-0002-3221-0542
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Systems Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: National Center for Protein Science Shanghai and State Key Laboratory of Biochemistry, CAS, University of Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Shicheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Systems Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Peng
authors.identifier: 0000-0002-6471-2766
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Wu
authors.affiliation: National Center for Protein Science Shanghai and State Key Laboratory of Biochemistry, CAS, University of Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Ding
authors.affiliation: Key Laboratory of Systems Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ronggui
authors.initials: R
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China.|National Center for Protein Science Shanghai and State Key Laboratory of Biochemistry, CAS, University of Chinese Academy of Sciences, Shanghai 201203, China.|State Key Laboratory of Virology, Wuhan Institute of Virology, CAS, Wuhan 430071, China.
authors.forename: Bin
authors.identifier: 0000-0002-2731-489X
authors.initials: B
authors.lastname: Wei
authors.affiliation: Key Laboratory of Systems Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, University of Chinese Academy of Sciences, Shanghai 200031, China hongyanwang@sibcb.ac.cn.
authors.forename: Hongyan
authors.identifier: 0000-0002-4074-3699
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D002465:Cell Movement; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000502:physiology*; D009103:Multiple Sclerosis / Q000209:etiology; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*
chemical_list: C581598:Cdc42 protein, mouse; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C508643:LRCH1 protein, human; D008840:Microfilament Proteins; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha; D020764:cdc42 GTP-Binding Protein