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Ubiquitin-like protein 5 is a novel player in the UPR–PERK arm and ER stress–induced cell death
Biological functions of the highly conserved ubiquitin-like protein 5 (UBL5) are not well understood. In Caenorhabditis elegans, UBL5 is induced under mitochondrial stress to mount the mitochondrial unfolded protein response (UPR). However, the role of UBL5 in the more prevalent endoplasmic reticulu...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339194/ https://www.ncbi.nlm.nih.gov/pubmed/37315790 http://dx.doi.org/10.1016/j.jbc.2023.104915 |
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author | Wang, Wei Hawkridge, Adam M. Ma, Yibao Zhang, Bei Mangrum, John B. Hassan, Zaneera H. He, Tianhai Blat, Sofiya Guo, Chunqing Zhou, Huiping Liu, Jinze Wang, Xiang-Yang Fang, Xianjun |
author_facet | Wang, Wei Hawkridge, Adam M. Ma, Yibao Zhang, Bei Mangrum, John B. Hassan, Zaneera H. He, Tianhai Blat, Sofiya Guo, Chunqing Zhou, Huiping Liu, Jinze Wang, Xiang-Yang Fang, Xianjun |
author_sort | Wang, Wei |
collection | PubMed |
description | Biological functions of the highly conserved ubiquitin-like protein 5 (UBL5) are not well understood. In Caenorhabditis elegans, UBL5 is induced under mitochondrial stress to mount the mitochondrial unfolded protein response (UPR). However, the role of UBL5 in the more prevalent endoplasmic reticulum (ER) stress-UPR in the mammalian system is unknown. In the present work, we demonstrated that UBL5 was an ER stress–responsive protein, undergoing rapid depletion in mammalian cells and livers of mice. The ER stress–induced UBL5 depletion was mediated by proteasome-dependent yet ubiquitin-independent proteolysis. Activation of the protein kinase R–like ER kinase arm of the UPR was essential and sufficient for inducing UBL5 degradation. RNA-Seq analysis of UBL5-regulated transcriptome revealed that multiple death pathways were activated in UBL5-silenced cells. In agreement with this, UBL5 knockdown induced severe apoptosis in culture and suppressed tumorigenicity of cancer cells in vivo. Furthermore, overexpression of UBL5 protected specifically against ER stress–induced apoptosis. These results identify UBL5 as a physiologically relevant survival regulator that is proteolytically depleted by the UPR-protein kinase R–like ER kinase pathway, linking ER stress to cell death. |
format | Online Article Text |
id | pubmed-10339194 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-103391942023-07-14 Ubiquitin-like protein 5 is a novel player in the UPR–PERK arm and ER stress–induced cell death Wang, Wei Hawkridge, Adam M. Ma, Yibao Zhang, Bei Mangrum, John B. Hassan, Zaneera H. He, Tianhai Blat, Sofiya Guo, Chunqing Zhou, Huiping Liu, Jinze Wang, Xiang-Yang Fang, Xianjun J Biol Chem Research Article Biological functions of the highly conserved ubiquitin-like protein 5 (UBL5) are not well understood. In Caenorhabditis elegans, UBL5 is induced under mitochondrial stress to mount the mitochondrial unfolded protein response (UPR). However, the role of UBL5 in the more prevalent endoplasmic reticulum (ER) stress-UPR in the mammalian system is unknown. In the present work, we demonstrated that UBL5 was an ER stress–responsive protein, undergoing rapid depletion in mammalian cells and livers of mice. The ER stress–induced UBL5 depletion was mediated by proteasome-dependent yet ubiquitin-independent proteolysis. Activation of the protein kinase R–like ER kinase arm of the UPR was essential and sufficient for inducing UBL5 degradation. RNA-Seq analysis of UBL5-regulated transcriptome revealed that multiple death pathways were activated in UBL5-silenced cells. In agreement with this, UBL5 knockdown induced severe apoptosis in culture and suppressed tumorigenicity of cancer cells in vivo. Furthermore, overexpression of UBL5 protected specifically against ER stress–induced apoptosis. These results identify UBL5 as a physiologically relevant survival regulator that is proteolytically depleted by the UPR-protein kinase R–like ER kinase pathway, linking ER stress to cell death. American Society for Biochemistry and Molecular Biology 2023-06-12 /pmc/articles/PMC10339194/ /pubmed/37315790 http://dx.doi.org/10.1016/j.jbc.2023.104915 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Wang, Wei Hawkridge, Adam M. Ma, Yibao Zhang, Bei Mangrum, John B. Hassan, Zaneera H. He, Tianhai Blat, Sofiya Guo, Chunqing Zhou, Huiping Liu, Jinze Wang, Xiang-Yang Fang, Xianjun Ubiquitin-like protein 5 is a novel player in the UPR–PERK arm and ER stress–induced cell death |
title | Ubiquitin-like protein 5 is a novel player in the UPR–PERK arm and ER stress–induced cell death |
title_full | Ubiquitin-like protein 5 is a novel player in the UPR–PERK arm and ER stress–induced cell death |
title_fullStr | Ubiquitin-like protein 5 is a novel player in the UPR–PERK arm and ER stress–induced cell death |
title_full_unstemmed | Ubiquitin-like protein 5 is a novel player in the UPR–PERK arm and ER stress–induced cell death |
title_short | Ubiquitin-like protein 5 is a novel player in the UPR–PERK arm and ER stress–induced cell death |
title_sort | ubiquitin-like protein 5 is a novel player in the upr–perk arm and er stress–induced cell death |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339194/ https://www.ncbi.nlm.nih.gov/pubmed/37315790 http://dx.doi.org/10.1016/j.jbc.2023.104915 |
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