ECPAS/Ecm29-mediated 26S proteasome disassembly is an adaptive response to glucose starvation

Won Hoon Choi; Yejin Yun; Insuk Byun; Sumin Kim; Seho Lee; Jiho Sim; Shahar Levi; Seo Hyeong Park; Jeongmoo Jun; Oded Kleifeld; Kwang Pyo Kim; Dohyun Han; Tomoki Chiba; Chaok Seok; Yong Tae Kwon; Michael H Glickman; Min Jae Lee

doi:10.1016/j.celrep.2023.112701

ECPAS/Ecm29-mediated 26S proteasome disassembly is an adaptive response to glucose starvation

Cell Rep. 2023 Jul 25;42(7):112701. doi: 10.1016/j.celrep.2023.112701. Epub 2023 Jun 27.

Authors

Won Hoon Choi¹, Yejin Yun², Insuk Byun², Sumin Kim², Seho Lee³, Jiho Sim³, Shahar Levi⁴, Seo Hyeong Park², Jeongmoo Jun¹, Oded Kleifeld⁴, Kwang Pyo Kim⁵, Dohyun Han⁶, Tomoki Chiba⁷, Chaok Seok³, Yong Tae Kwon⁸, Michael H Glickman⁹, Min Jae Lee¹⁰

Affiliations

¹ Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
² Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
³ Department of Chemistry, Seoul National University, Seoul 08826, Korea.
⁴ Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
⁵ Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Korea.
⁶ Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea.
⁷ Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8577, Japan.
⁸ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea; Ischemic/Hypoxic Disease Institute, Convergence Research Center for Dementia, Seoul National University College of Medicine, Seoul 03080, Korea.
⁹ Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel. Electronic address: glickman@technion.ac.il.
¹⁰ Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea; Ischemic/Hypoxic Disease Institute, Convergence Research Center for Dementia, Seoul National University College of Medicine, Seoul 03080, Korea. Electronic address: minjlee@snu.ac.kr.

PMID: 37384533
DOI: 10.1016/j.celrep.2023.112701

Abstract

The 26S proteasome comprises 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in cells exist as free 20S complexes; however, our mechanistic understanding of what determines the ratio of 26S to 20S species remains incomplete. Here, we show that glucose starvation uncouples 26S holoenzymes into 20S and 19S subcomplexes. Subcomplex affinity purification and quantitative mass spectrometry reveal that Ecm29 proteasome adaptor and scaffold (ECPAS) mediates this structural remodeling. The loss of ECPAS abrogates 26S dissociation, reducing degradation of 20S proteasome substrates, including puromycylated polypeptides. In silico modeling suggests that ECPAS conformational changes commence the disassembly process. ECPAS is also essential for endoplasmic reticulum stress response and cell survival during glucose starvation. In vivo xenograft model analysis reveals elevated 20S proteasome levels in glucose-deprived tumors. Our results demonstrate that the 20S-19S disassembly is a mechanism adapting global proteolysis to physiological needs and countering proteotoxic stress.

Keywords: 19S complex; 20S proteasome; CP: Metabolism; ECPAS; Ecm29; disassembly; glucose; in silico modeling; proteasome; proteolysis; starvation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cytoplasm / metabolism
Humans
Mass Spectrometry
Proteasome Endopeptidase Complex* / metabolism
Proteolysis

Substances

ATP dependent 26S protease
Proteasome Endopeptidase Complex