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Reduced lysosomal clearance of autophagosomes promotes survival and colonization of Helicobacter pylori.

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机构: [1]Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [2]Institute of Digestive Diseases, State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [3]Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China. [4]School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [5]Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [6]The Roslin Institute, University of Edinburgh, Edinburgh, UK. [7]Department of Microbiology, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [8]Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [9]The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [10]Department of Medicine, Howard University, Washington, DC, USA. [11]Cancer Center, Howard University, Washington, DC, USA. [12]Howard University Hospital, Howard University, Washington, DC, USA. [13]Department of Internal Medicine, Meharry Medical College, Nashville, TN, USA.
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关键词: Helicobacter xenophagy subversion lysosome

摘要:
Evasion of autophagy is key for intracellular survival of bacteria in host cells, but its involvement in persistent infection by Helicobacter pylori, a bacterium identified to invade gastric epithelial cells, remains obscure. The aim of this study was to functionally characterize the role of autophagy in H. pylori infection. Autophagy was assayed in H. pylori-infected human gastric epithelium and the functional role of autophagy was determined via genetic or pharmacological ablation of autophagy in mouse and cell line models of H. pylori infection. Here, we showed that H. pylori inhibited lysosomal function and thereby promoted the accumulation of autophagosomes in gastric epithelial cells. Importantly, inhibiting autophagosome formation by pharmacological inhibitors or genetic ablation of BECN1 or ATG5 reduced H. pylori intracellular survival, whereas inhibition of lysosomal functions exerted an opposite effect. Further experiments demonstrated that H. pylori inhibited lysosomal acidification and the retrograde trafficking of mannose-6-phosphate receptors, both of which are known to positively regulate lysosomal function. We conclude that H. pylori subverts autophagy into a pro-survival mechanism through inhibition of lysosomal clearance of autophagosomes. Disruption of autophagosome formation offers a novel strategy to reduce H. pylori colonization in human stomachs. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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出版当年[2018]版:
大类 | 1 区 医学
小类 | 1 区 病理学 2 区 肿瘤学
最新[2023]版:
大类 | 2 区 医学
小类 | 1 区 病理学 2 区 肿瘤学
第一作者:
第一作者机构: [1]Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [2]Institute of Digestive Diseases, State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [3]Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.
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通讯作者:
通讯机构: [1]Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [2]Institute of Digestive Diseases, State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [8]Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [*1]Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, PR China. [*2]Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
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