沙门氏菌诱导的胆固醇在受感染巨噬细胞中积累,通过激活 mTORC1 抑制自噬。

IF 3.1 3区 生物学 Q3 CELL BIOLOGY
Molecular Biology of the Cell Pub Date : 2025-01-01 Epub Date: 2024-11-27 DOI:10.1091/mbc.E24-06-0283
Holly M Torsilieri, Clint M Upchurch, Norbert Leitinger, James E Casanova
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引用次数: 0

摘要

鼠伤寒沙门氏菌是一种革兰氏阴性杆菌,可感染宿主肠上皮细胞和常驻巨噬细胞。许多细胞内病原体会诱导宿主细胞产生自噬反应,但它们也进化出了颠覆这种反应的机制。自噬与细胞胆固醇水平密切相关;mTORC1 能感知溶酶体膜中胆固醇的增加,导致其过度活跃并抑制自噬。以前的研究表明,沙门氏菌感染会诱导巨噬细胞中胆固醇的急剧积累,其中一部分胆固醇会定位于含沙门氏菌的空泡(SCVs)中。我们以前曾报道细菌效应蛋白 SseJ 通过涉及 Focal Adhesion Kinase(FAK)和 Akt 的信号级联引发胆固醇积累。在这里,我们发现 mTORC1 被招募到 SCV,并以胆固醇依赖的方式被过度激活。如果用药物或通过突变 sseJ 来阻止胆固醇的积累,自噬就会被诱导,细菌的存活率就会降低。值得注意的是,宿主脂质转移蛋白 OSBP 也被招募到 SCV 上,其活性对于胆固醇转移到 SCV 和感染期间 mTORC1 的激活都是必需的。最后,对沙门氏菌感染的巨噬细胞进行的脂质组学分析揭示了沙门氏菌如何操纵脂质稳态以利于其生存的新见解。我们提出,伤寒沙门氏菌通过 SseJ 诱导胆固醇积累,从而激活 mTORC1,阻止细菌的自噬清除。[媒体:见正文]。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Salmonella-induced cholesterol accumulation in infected macrophages suppresses autophagy via mTORC1 activation.

Salmonella enterica serovar Typhimurium is a Gram-negative bacillus that infects the host intestinal epithelium and resident macrophages. Many intracellular pathogens induce an autophagic response in host cells but have evolved mechanisms to subvert that response. Autophagy is closely linked to cellular cholesterol levels; mTORC1 senses increased cholesterol in lysosomal membranes, leading to its hyperactivity and suppression of autophagy. Previous studies indicate that Salmonella infection induces dramatic accumulation of cholesterol in macrophages, a fraction of which localizes to Salmonella containing vacuoles (SCVs). We previously reported that the bacterial effector protein SseJ triggers cholesterol accumulation through a signaling cascade involving focal adhesion kinase (FAK) and Akt. Here we show that mTORC1 is recruited to SCVs and is hyperactivated in a cholesterol-dependent manner. If cholesterol accumulation is prevented pharmacologically or through mutation of sseJ, autophagy is induced and bacterial survival is attenuated. Notably, the host lipid transfer protein OSBP (oxysterol binding protein 1) is also recruited to SCVs and its activity is necessary for both cholesterol transfer to SCVs and mTORC1 activation during infection. Finally, lipidomic analysis of Salmonella-infected macrophages revealed new insights into how Salmonella may manipulate lipid homeostasis to benefit its survival. We propose that S. Typhimurium induces cholesterol accumulation through SseJ to activate mTORC1, preventing autophagic clearance of bacteria.

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来源期刊
Molecular Biology of the Cell
Molecular Biology of the Cell 生物-细胞生物学
CiteScore
6.00
自引率
6.10%
发文量
402
审稿时长
2 months
期刊介绍: MBoC publishes research articles that present conceptual advances of broad interest and significance within all areas of cell, molecular, and developmental biology. We welcome manuscripts that describe advances with applications across topics including but not limited to: cell growth and division; nuclear and cytoskeletal processes; membrane trafficking and autophagy; organelle biology; quantitative cell biology; physical cell biology and mechanobiology; cell signaling; stem cell biology and development; cancer biology; cellular immunology and microbial pathogenesis; cellular neurobiology; prokaryotic cell biology; and cell biology of disease.
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