Derlin-1 and TER94/VCP/p97 are required for intestinal homeostasis

Fuli Liu; Hang Zhao; Ruiyan Kong; Lin Shi; Zhengran Li; Rui Ma; Huiqing Zhao; Zhouhua Li

doi:10.1016/j.jgg.2021.08.017

Volume 49 Issue 3

Mar. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(3): 195-207

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Derlin-1 and TER94/VCP/p97 are required for intestinal homeostasis

doi: 10.1016/j.jgg.2021.08.017

a College of Life Sciences, Capital Normal University, Beijing 100048, China;
b Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China

Funds:

We are grateful to Norbert Perrimon, Steven Hou, Zhaohui Liu, Lei Liu, Lilla Fang, Jose Paster, and Yu Cai for generous gifts of reagents, the Bloomington Stock Center, TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947), Tsinghua Fly Center (THFC) and Kyoto Stock Center for fly stocks, DSHB for antibodies and BDGP for cDNA clones. We apologize to the colleagues whose work could not be cited because of space restrictions. This work is supported by grants from the National Natural Science Foundation of China (31972893, 92054109 and 31471384) and Beijing Municipal Commission of Education (No KZ201910028040) and Beijing Natural Science Fundation (No 5162004).

Received Date: 2021-05-06
Accepted Date: 2021-08-19
Rev Recd Date: 2021-08-15
Publish Date: 2021-09-20

Abstract

Abstract

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 TER94/VCP/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.
- Derlin-1,
- TER94/VCP/p97,
- ERAD,
- Intestinal homeostasis,
- Drosophila

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References(71)

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