NFκB 和 JNK 通路在 ESCRT-I 缺乏时介导代谢适应。

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cellular and Molecular Life Sciences Pub Date : 2024-11-19 DOI:10.1007/s00018-024-05490-y
Jaroslaw Cendrowski, Marta Wrobel, Michal Mazur, Bartosz Jary, Ranjana Maurya, Surui Wang, Michal Korostynski, Anna Dziewulska, Maria Rohm, Patryk Kuropka, Natalia Pudelko-Malik, Piotr Mlynarz, Agnieszka Dobrzyn, Anja Zeigerer, Marta Miaczynska
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引用次数: 0

摘要

运输所需的内体分拣复合物(ESCRTs)对于运送膜受体或细胞内细胞器供溶酶体降解至关重要,而溶酶体降解可为细胞提供源于溶酶体的营养物质。然而,ESCRT 功能障碍如何影响细胞的新陈代谢仍是一个未知数。为了解决这个问题,我们分析了缺乏 TSG101 或 VPS28 蛋白(ESCRT-I 亚复合物的组成成分)的细胞的转录组。缺乏ESCRT-I会降低参与脂肪酸和氨基酸(如支链氨基酸)氧化的酶编码基因的表达,并增加糖酵解酶编码基因的表达。代谢基因表达的变化与类似沃伯格效应的代谢重编程有关,其中包括细胞内脂类的积累、葡萄糖/谷氨酰胺消耗的增加和乳酸盐的产生。此外,ESCRT-I成分的耗竭导致ER扩大和小线粒体的积累,其中大部分线粒体保持适当的电位并进行与ATP相关的呼吸。从机理上讲,在缺乏 ESCRT-I 的情况下,由于激活了典型的 NFκB 和 JNK 信号通路,并至少部分地通过扰乱溶酶体降解,观察到了转录向糖酵解的重编程。我们认为,通过激活应激信号通路,ESCRT-I 缺乏会导致细胞外营养物质(如葡萄糖和谷氨酰胺)优先用于产生能量,而不是溶酶体衍生的营养物质(如脂肪酸和支链氨基酸)。
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NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency.

Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation which provides the cell with lysosome-derived nutrients. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, such as branched-chain amino acids, and increased the expression of genes encoding glycolytic enzymes. The changes in metabolic gene expression were associated with Warburg effect-like metabolic reprogramming that included intracellular accumulation of lipids, increased glucose/glutamine consumption and lactate production. Moreover, depletion of ESCRT-I components led to expansion of the ER and accumulation of small mitochondria, most of which retained proper potential and performed ATP-linked respiration. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways and at least in part by perturbed lysosomal degradation. We propose that by activating the stress signaling pathways ESCRT-I deficiency leads to preferential usage of extracellular nutrients, like glucose and glutamine, for energy production instead of lysosome-derived nutrients, such as fatty acids and branched-chain amino acids.

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来源期刊
Cellular and Molecular Life Sciences
Cellular and Molecular Life Sciences 生物-生化与分子生物学
CiteScore
13.20
自引率
1.20%
发文量
546
审稿时长
1.0 months
期刊介绍: Journal Name: Cellular and Molecular Life Sciences (CMLS) Location: Basel, Switzerland Focus: Multidisciplinary journal Publishes research articles, reviews, multi-author reviews, and visions & reflections articles Coverage: Latest aspects of biological and biomedical research Areas include: Biochemistry and molecular biology Cell biology Molecular and cellular aspects of biomedicine Neuroscience Pharmacology Immunology Additional Features: Welcomes comments on any article published in CMLS Accepts suggestions for topics to be covered
期刊最新文献
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