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Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis

RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53(+/)(−) mice by triggering genome instability and sensitized Trp53(+/)(−) mice to radi...

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Autores principales: Xiong, Xiufang, Liu, Xia, Li, Haomin, He, Hengqian, Sun, Yi, Zhao, Yongchao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234217/
https://www.ncbi.nlm.nih.gov/pubmed/30425236
http://dx.doi.org/10.1038/s41419-018-1168-7
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author Xiong, Xiufang
Liu, Xia
Li, Haomin
He, Hengqian
Sun, Yi
Zhao, Yongchao
author_facet Xiong, Xiufang
Liu, Xia
Li, Haomin
He, Hengqian
Sun, Yi
Zhao, Yongchao
author_sort Xiong, Xiufang
collection PubMed
description RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53(+/)(−) mice by triggering genome instability and sensitized Trp53(+/)(−) mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis.
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spelling pubmed-62342172018-11-14 Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis Xiong, Xiufang Liu, Xia Li, Haomin He, Hengqian Sun, Yi Zhao, Yongchao Cell Death Dis Article RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53(+/)(−) mice by triggering genome instability and sensitized Trp53(+/)(−) mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis. Nature Publishing Group UK 2018-11-13 /pmc/articles/PMC6234217/ /pubmed/30425236 http://dx.doi.org/10.1038/s41419-018-1168-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xiong, Xiufang
Liu, Xia
Li, Haomin
He, Hengqian
Sun, Yi
Zhao, Yongchao
Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis
title Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis
title_full Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis
title_fullStr Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis
title_full_unstemmed Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis
title_short Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis
title_sort ribosomal protein s27-like regulates autophagy via the β-trcp-deptor-mtorc1 axis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234217/
https://www.ncbi.nlm.nih.gov/pubmed/30425236
http://dx.doi.org/10.1038/s41419-018-1168-7
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