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SNX10-mediated LPS sensing causes intestinal barrier dysfunction via a caspase-5-dependent signaling cascade

文献类型：期刊论文

作者Wang, Xu1,2; Ni, Jiahui1,2,3; You, Yan1,2; Feng, Guize1,2; Zhang, Sulin4; Bao, Weilian1,2; Hou, Hui4; Li, Haidong1,2; Liu, Lixin1,2; Zheng, Mingyue4
刊名EMBO JOURNAL
出版日期2021-11-08
页码16
ISSN号0261-4189
关键词E-cadherin IBD intestinal barrier function LPS release SNX10
DOI10.15252/embj.2021108080
通讯作者Zhou, Hua() ; Shen, Weixing(weixingshen@njucm.edu.cn) ; Shen, Xiaoyan(shxiaoy@fudan.edu.cn)
英文摘要Altered intestinal microbial composition promotes intestinal barrier dysfunction and triggers the initiation and recurrence of inflammatory bowel disease (IBD). Current treatments for IBD are focused on control of inflammation rather than on maintaining intestinal epithelial barrier function. Here, we show that the internalization of Gram-negative bacterial outer membrane vesicles (OMVs) in human intestinal epithelial cells promotes recruitment of caspase-5 and PIKfyve to early endosomal membranes via sorting nexin 10 (SNX10), resulting in LPS release from OMVs into the cytosol. Caspase-5 activated by cytosolic LPS leads to Lyn phosphorylation, which in turn promotes nuclear translocalization of Snail/Slug, downregulation of E-cadherin expression, and intestinal barrier dysfunction. SNX10 deletion or treatment with DC-SX029, a novel SNX10 inhibitor, rescues OMV-induced intestinal barrier dysfunction and ameliorates colitis in mice by blocking cytosolic LPS release, caspase-5 activation, and downstream signaling. Our results show that targeting SNX10 may be a new therapeutic approach for restoring intestinal epithelial barrier function and promising strategy for IBD treatment.
WOS关键词CROHNS-DISEASE ; SUSCEPTIBILITY LOCI ; MULTIPLE ; BINDING ; PERMEABILITY ; ACTIVATION
资助项目National Natural Science Foundation of China[82130108] ; National Natural Science Foundation of China[81773744] ; National Natural Science Foundation of China[81973523] ; National Natural Science Foundation of China[81573441] ; National Natural Science Foundation of China[81371923] ; Shanghai Pujiang Program[21PJ1401400] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020368] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1903KF-05] ; Fudan-SIMM Joint Research Fund[FU-SIMM20183002]
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
出版者WILEY
WOS记录号WOS:000715243400001
源URL[http://119.78.100.183/handle/2S10ELR8/298774]  
专题新药研究国家重点实验室
通讯作者Zhou, Hua; Shen, Weixing; Shen, Xiaoyan
作者单位1.Fudan Univ, Sch Pharm, Dept Pharmacol, Minist Educ, Shanghai, Peoples R China
2.Fudan Univ, Sch Pharm, Key Lab Smart Drug Delivery, Minist Educ, Shanghai, Peoples R China
3.Nanjing Univ Chinese Med, Clin Med Coll 1, Jiangsu Collaborat Innovat Ctr Tradit Chinese Med, Nanjing, Peoples R China
4.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
5.Macau Univ Sci & Technol, Fac Chinese Med, Taipa, Macao, Peoples R China
6.Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Taipa, Macao, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Xu,Ni, Jiahui,You, Yan,et al. SNX10-mediated LPS sensing causes intestinal barrier dysfunction via a caspase-5-dependent signaling cascade[J]. EMBO JOURNAL,2021:16.
APA Wang, Xu.,Ni, Jiahui.,You, Yan.,Feng, Guize.,Zhang, Sulin.,...&Shen, Xiaoyan.(2021).SNX10-mediated LPS sensing causes intestinal barrier dysfunction via a caspase-5-dependent signaling cascade.EMBO JOURNAL,16.
MLA Wang, Xu,et al."SNX10-mediated LPS sensing causes intestinal barrier dysfunction via a caspase-5-dependent signaling cascade".EMBO JOURNAL (2021):16.

入库方式： OAI收割

来源：上海药物研究所

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