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脂质稳态受损通过内体分选转运复合体（ESCRT）破坏导致内源性蛋白质聚集体在溶酶体中积累。

Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption.

作者信息

Yong John, Villalta Jacqueline E, Vu Ngoc, Kukurugya Matthew A, Olsson Niclas, López Magdalena Preciado, Lazzari-Dean Julia R, Hake Kayley, McAllister Fiona E, Bennett Bryson D, Jan Calvin H

机构信息

Calico Life Sciences LLC, South San Francisco, United States.

出版信息

Elife. 2024 Dec 23;12:RP86194. doi: 10.7554/eLife.86194.

DOI:10.7554/eLife.86194
PMID:39713930
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11666243/
Abstract

Protein aggregation increases during aging and is a pathological hallmark of many age-related diseases. Protein homeostasis (proteostasis) depends on a core network of factors directly influencing protein production, folding, trafficking, and degradation. Cellular proteostasis also depends on the overall composition of the proteome and numerous environmental variables. Modulating this cellular proteostasis state can influence the stability of multiple endogenous proteins, yet the factors contributing to this state remain incompletely characterized. Here, we performed genome-wide CRISPRi screens to elucidate the modulators of proteostasis state in mammalian cells, using a fluorescent dye to monitor endogenous protein aggregation. These screens identified known components of the proteostasis network and uncovered a novel link between protein and lipid homeostasis. Increasing lipid uptake and/or disrupting lipid metabolism promotes the accumulation of sphingomyelins and cholesterol esters and drives the formation of detergent-insoluble protein aggregates at the lysosome. Proteome profiling of lysosomes revealed ESCRT accumulation, suggesting disruption of ESCRT disassembly, lysosomal membrane repair, and microautophagy. Lipid dysregulation leads to lysosomal membrane permeabilization but does not otherwise impact fundamental aspects of lysosomal and proteasomal functions. Together, these results demonstrate that lipid dysregulation disrupts ESCRT function and impairs proteostasis.

摘要

蛋白质聚集在衰老过程中增加，是许多与年龄相关疾病的病理标志。蛋白质稳态（proteostasis）依赖于直接影响蛋白质产生、折叠、运输和降解的核心因子网络。细胞蛋白质稳态还取决于蛋白质组的整体组成和众多环境变量。调节这种细胞蛋白质稳态状态可影响多种内源性蛋白质的稳定性，然而导致这种状态的因素仍未完全明确。在此，我们进行了全基因组CRISPR干扰筛选，以阐明哺乳动物细胞中蛋白质稳态状态的调节因子，使用一种荧光染料来监测内源性蛋白质聚集。这些筛选确定了蛋白质稳态网络的已知成分，并揭示了蛋白质和脂质稳态之间的新联系。增加脂质摄取和/或破坏脂质代谢会促进鞘磷脂和胆固醇酯的积累，并在溶酶体处驱动形成去污剂不溶性蛋白质聚集体。溶酶体的蛋白质组分析显示内体分选转运复合体（ESCRT）积累，表明ESCRT拆卸、溶酶体膜修复和微自噬受到破坏。脂质失调导致溶酶体膜通透性增加，但不会以其他方式影响溶酶体和蛋白酶体功能的基本方面。总之，这些结果表明脂质失调会破坏ESCRT功能并损害蛋白质稳态。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2665/11666243/666a16a66232/elife-86194-fig7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2665/11666243/666a16a66232/elife-86194-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2665/11666243/c1bc6f9b9b13/elife-86194-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2665/11666243/556b6e5d9426/elife-86194-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2665/11666243/070e9d937574/elife-86194-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2665/11666243/27cddc517a71/elife-86194-fig2-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2665/11666243/eb93dcb74d47/elife-86194-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2665/11666243/666a16a66232/elife-86194-fig7.jpg

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