Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-04-08 DOI:10.1016/j.cell.2025.03.009

Andrew Murley, Ann Catherine Popovici, Xiwen Sophie Hu, Anina Lund, Kevin Wickham, Jenni Durieux, Larry Joe, Etai Koronyo, Hanlin Zhang, Naomi R. Genuth, Andrew Dillin

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Abstract

To maintain tissue homeostasis, many cells reside in a quiescent state until prompted to divide. The reactivation of quiescent cells is perturbed with aging and may underlie declining tissue homeostasis and resiliency. The unfolded protein response regulators IRE-1 and XBP-1 are required for the reactivation of quiescent cells in developmentally L1-arrested C. elegans. Utilizing a forward genetic screen in C. elegans, we discovered that macroautophagy targets protein aggregates to lysosomes in quiescent cells, leading to lysosome damage. Genetic inhibition of macroautophagy and stimulation of lysosomes via the overexpression of HLH-30 (TFEB/TFE3) synergistically reduces lysosome damage. Damaged lysosomes require IRE-1/XBP-1 for their repair following prolonged L1 arrest. Protein aggregates are also targeted to lysosomes by macroautophagy in quiescent cultured mammalian cells and are associated with lysosome damage. Thus, lysosome damage is a hallmark of quiescent cells, and limiting lysosome damage by restraining macroautophagy can stimulate their reactivation.

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静止细胞的再入受到巨噬诱导的溶酶体损伤的限制

为了维持组织的稳态，许多细胞处于静止状态，直到被催促分裂。随着年龄的增长，静止细胞的重新激活会受到干扰，这可能是组织平衡和恢复能力下降的原因。未折叠蛋白反应调节因子 IRE-1 和 XBP-1 是发育停滞的 elegans 中静止细胞重新活化所必需的。通过对 elegans 进行前向遗传筛选，我们发现大自噬会将静止细胞中的蛋白质聚集体靶向溶酶体，从而导致溶酶体损伤。基因抑制大自噬和通过过量表达 HLH-30 (TFEB/TFE3) 刺激溶酶体可协同减少溶酶体损伤。在 L1 长时间停滞后，受损的溶酶体需要 IRE-1/XBP-1 进行修复。在静止培养的哺乳动物细胞中，蛋白质聚集体也会通过大自噬作用靶向溶酶体，并与溶酶体损伤有关。因此，溶酶体损伤是静止细胞的一个特征，而通过抑制大自噬来限制溶酶体损伤可以刺激溶酶体的重新激活。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.