Derlin-1 and TER94/VCP/p97 are required for intestinal homeostasis
Derlin-1 and TER94/VCP/p97 are required for intestinal homeostasis
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DOI：
10.1016/j.jgg.2021.08.017
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发表时间：
2022-03-28
影响因子：
5.9
通讯作者：
Li, Zhouhua
中科院分区：
文献类型：
--
作者：
Liu, Fuli;Zhao, Hang;Li, Zhouhua
成体干细胞是维持居住组织稳态和功能的关键。然而，细胞蛋白稳态维持在干细胞增殖和组织稳态中的作用尚不完全清楚。本研究发现，作为内质网（ER）相关降解（ERAD）途径的组分，Derlin-1和TER94NCP/p97可抑制肠道干细胞增殖，维持成年果蝇肠道内稳态。消耗它们中的任何一种都会导致干细胞增殖增加和中肠稳态破坏。Derlin-1特异性定位于祖细胞的内质网，其c端是其功能所必需的。有趣的是，我们发现干细胞增殖的增加是由于Derlin-1或ter94缺陷祖细胞中ROS水平升高和JNK信号激活引起的。进一步去除活性氧（ROS）或抑制JNK信号几乎完全抑制了干细胞增殖的增加。综上所述，这些数据表明ERAD通路对干细胞增殖和组织稳态至关重要。因此，我们对组织稳态和肿瘤发展中细胞蛋白稳态维持（内质网蛋白质量控制）的机制的理解提供了见解。中国科学院遗传与发育生物学研究所，中国遗传学会版权所有2021爱思唯尔有限公司和科学出版社出版。版权所有。
Adult stem cells are critical for the maintenance of residential tissue homeostasis and functions. However, the roles of cellular protein homeostasis maintenance in stem cell proliferation and tissue homeostasis are not fully understood. Here, we find that Derlin-1 and TER94NCP/p97, components of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, restrain intestinal stem cell proliferation to maintain intestinal homeostasis in adult Drosophila. Depleting any of them results in increased stem cell proliferation and midgut homeostasis disruption. Derlin-1 is specifically localized in the ER of progenitors, and its C-terminus is required for its function. Interestingly, we find that increased stem cell proliferation is resulted from elevated ROS levels and activated JNK signaling in Derlin-1- or TER94-deficient progenitors. Further removal of reactive oxygen species (ROS) or inhibition of JNK signaling almost completely suppresses increased stem cell proliferation. Together, these data demonstrate that the ERAD pathway is critical for stem cell proliferation and tissue homeostasis. Thus, we provide insights into our understanding of the mechanisms underlying cellular protein homeostasis maintenance (ER protein quality control) in tissue homeostasis and tumor development. Copyright (C) 2021, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.