| .调控宿主线粒体未折叠蛋白反应的细菌筛选及机制研究[J].,2024,(24):4601-4607 |
| 调控宿主线粒体未折叠蛋白反应的细菌筛选及机制研究 |
| A Systems Level Analysis of Communications between Microbes and Host Mitochondrial Unfolded Protein Response |
| 投稿时间：2024-08-12 修订日期：2024-09-13 |
| DOI：10.13241/j.cnki.pmb.2024.24.001 |
| 中文关键词: 秀丽线虫 大肠杆菌 宿主-肠道菌互作 线粒体未折叠蛋白反应 铁代谢 |
| 英文关键词: C. elegans Escherichia coli Microbe-host interaction Mitochondrial unfolded protein response Iron metabolism |
| 基金项目:国家重点研发计划项目（2021YFC2701100）；国家自然科学基金项目（32271215）；重庆市教委科技项目（KJQN202300306） |
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| 中文摘要: |
| 摘要 目的：筛选调控宿主线粒体未折叠蛋白反应的细菌，探究不同种属的细菌及细菌突变体调控宿主线粒体未折叠蛋白反应的分子机制。方法：我们开发了一种在体的高通量筛选及分析方法，评估细菌对宿主线粒体未折叠蛋白反应的影响。通过筛选不同种属的细菌及3985个单基因敲除的大肠杆菌突变体，鉴定出调控秀丽线虫线粒体未折叠蛋白反应的细菌。结果：通过筛选及验证，我们鉴定出88个大肠杆菌基因突变体及农球菌R98激活秀丽线虫线粒体未折叠蛋白反应。88个大肠杆菌基因参与多种细胞过程，包括信号转导、RNA修饰和运输等。值得注意的是，40%的基因与细菌代谢相关。fepG编码铁载体ABC转运蛋白亚基，对于细菌从环境中获取铁至关重要。我们给△fepG 等细菌突变体补充铁可以抑制大肠杆菌诱导的秀丽线虫线粒体未折叠蛋白反应，表明大肠杆菌的铁代谢调控秀丽线虫的线粒体未折叠蛋白反应。补充铁不能抑制农球菌R98诱导的宿主线粒体未折叠蛋白反应，证明不同种属的菌株激发宿主线粒体折叠蛋白反应的机制不同。结论：我们的研究揭示了不同细菌调控宿主线粒体未折叠蛋白反应的分子机制，并为高等生物中的研究奠定了基础。 |
| 英文摘要: |
| ABSTRACT Objective: Mitochondrial dysfunction is widely implicated in various diseases and pathological conditions. The mitochondrial unfolded protein response (UPR mt ) is activated to maintain mitochondrial function when misfolded proteins accumulate. Recent findings have unveiled several factors that activate UPR mt . However, the precise mechanism underlying UPR mt activation by microbes, remains incompletely understood. To identify bacterial modifiers of host mitochondrial unfolded protein response. Methods: We developed an in vivo high-throughput screening assay to assess the impact of microbes on host mitochondrial unfolded protein response. We screened 3985 Escherichia coli single-gene deleted mutants. Results: Through first screening and further validation, we identified 88 E. coli single-gene deleted mutants and Agrococcus R98 that regulate UPR mt in C. elegans. 88 E. coli genes are involved in various cellular processes, including signal transduction, RNA modification, and transport. Notably, 40% of these genes are related to bacterial metabolism. fepG encodes a ferric enterobactin ABC transporter subunit, essential for retrieving insoluble Fe(III) from environments. We supplemented C. elegans fed △fepG and other mutants with the iron and observed a repression of host UPR mt , suggesting that bacteria act through iron to trigger C. elegans mitochondrial unfolded protein response. However, iron supplementation did not inhibit the host UPR mt induced by Agrococcus R98, demonstrating that different species of bacteria stimulate the host UPR mt by different mechanisms. Conclusion: Our study sheds light on a systems-level understanding of how microbial metabolites regulate host mitochondrial unfolded protein response, laying a foundation for similar investigations in higher organisms. |
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