静止细胞的再入受到巨噬诱导的溶酶体损伤的限制，这一成果由美国加州大学Andrew Dillin研究组经过不懈努力而取得。相关论文于2025年4月8日发表在《细胞》杂志上。

利用线虫的正向遗传筛选，该课题组人员发现巨噬作用的目标是蛋白质聚集到静止细胞的溶酶体，导致溶酶体损伤。通过过表达HLH-30 （TFEB/TFE3）对巨噬的遗传抑制和对溶酶体的刺激协同减少溶酶体损伤。受损的溶酶体需要IRE-1/XBP-1来修复长时间L1停搏后的溶酶体。在静止培养的哺乳动物细胞中，蛋白质聚集体也通过巨噬作用靶向溶酶体，并与溶酶体损伤有关。其中，溶酶体损伤是静止细胞的标志，通过抑制巨噬来限制溶酶体损伤可以刺激它们的再激活。

据了解，为了维持组织内稳态，许多细胞处于静止状态，直到分裂。静止细胞的再激活随着衰老而受到干扰，可能导致组织稳态和弹性下降。未折叠的蛋白反应调节因子IRE-1和XBP-1是发育中的秀丽隐杆线虫静止细胞再激活所必需的。

附：英文原文

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

Author: 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

Issue&Volume: 2025-04-08

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.

DOI: 10.1016/j.cell.2025.03.009

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00282-X