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Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration
Impaired transcription factor EB (TFEB) function and deficient autophagy activity have been shown to aggravate intervertebral disc (IVD) degeneration (IDD), yet the underlying mechanisms remain less clear. Protein posttranslational modifications (PTMs) are critical for determining TFEB trafficking a...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10482945/ https://www.ncbi.nlm.nih.gov/pubmed/37605006 http://dx.doi.org/10.1038/s41418-023-01210-4 |
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author | Liang, Huaizhen Luo, Rongjin Li, Gaocai Zhang, Weifeng Zhu, Dingchao Wu, Di Zhou, Xingyu Tong, Bide Wang, Bingjin Feng, Xiaobo Wang, Kun Song, Yu Yang, Cao |
author_facet | Liang, Huaizhen Luo, Rongjin Li, Gaocai Zhang, Weifeng Zhu, Dingchao Wu, Di Zhou, Xingyu Tong, Bide Wang, Bingjin Feng, Xiaobo Wang, Kun Song, Yu Yang, Cao |
author_sort | Liang, Huaizhen |
collection | PubMed |
description | Impaired transcription factor EB (TFEB) function and deficient autophagy activity have been shown to aggravate intervertebral disc (IVD) degeneration (IDD), yet the underlying mechanisms remain less clear. Protein posttranslational modifications (PTMs) are critical for determining TFEB trafficking and transcriptional activity. Here, we demonstrate that TFEB activity is controlled by protein methylation in degenerated nucleus pulposus cells (NPCs), even though TFEB itself is incapable of undergoing methylation. Specifically, protein phosphatase 1 catalytic subunit alpha (PPP1CA), newly identified to dephosphorylate TFEB, contains a K141 mono-methylated site. In degenerated NPCs, increased K141-methylation of PPP1CA disrupts its interaction with TEFB and subsequently blocks TEFB dephosphorylation and nuclear translocation, which eventually leads to autophagy deficiency and NPC senescence. In addition, we found that the PPP1CA-mediated targeting of TFEB is facilitated by the protein phosphatase 1 regulatory subunit 9B (PPP1R9B), which binds with PPP1CA and is also manipulated by K141 methylation. Further proteomic analysis revealed that the protein lysine methyltransferase suppressor of variegation 3–9 homologue 2 (SUV39H2) is responsible for the K141 mono-methylation of PPP1CA. Targeting SUV39H2 effectively mitigates NPC senescence and IDD progression, providing a potential therapeutic strategy for IDD intervention. |
format | Online Article Text |
id | pubmed-10482945 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104829452023-09-08 Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration Liang, Huaizhen Luo, Rongjin Li, Gaocai Zhang, Weifeng Zhu, Dingchao Wu, Di Zhou, Xingyu Tong, Bide Wang, Bingjin Feng, Xiaobo Wang, Kun Song, Yu Yang, Cao Cell Death Differ Article Impaired transcription factor EB (TFEB) function and deficient autophagy activity have been shown to aggravate intervertebral disc (IVD) degeneration (IDD), yet the underlying mechanisms remain less clear. Protein posttranslational modifications (PTMs) are critical for determining TFEB trafficking and transcriptional activity. Here, we demonstrate that TFEB activity is controlled by protein methylation in degenerated nucleus pulposus cells (NPCs), even though TFEB itself is incapable of undergoing methylation. Specifically, protein phosphatase 1 catalytic subunit alpha (PPP1CA), newly identified to dephosphorylate TFEB, contains a K141 mono-methylated site. In degenerated NPCs, increased K141-methylation of PPP1CA disrupts its interaction with TEFB and subsequently blocks TEFB dephosphorylation and nuclear translocation, which eventually leads to autophagy deficiency and NPC senescence. In addition, we found that the PPP1CA-mediated targeting of TFEB is facilitated by the protein phosphatase 1 regulatory subunit 9B (PPP1R9B), which binds with PPP1CA and is also manipulated by K141 methylation. Further proteomic analysis revealed that the protein lysine methyltransferase suppressor of variegation 3–9 homologue 2 (SUV39H2) is responsible for the K141 mono-methylation of PPP1CA. Targeting SUV39H2 effectively mitigates NPC senescence and IDD progression, providing a potential therapeutic strategy for IDD intervention. Nature Publishing Group UK 2023-08-21 2023-09 /pmc/articles/PMC10482945/ /pubmed/37605006 http://dx.doi.org/10.1038/s41418-023-01210-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Liang, Huaizhen Luo, Rongjin Li, Gaocai Zhang, Weifeng Zhu, Dingchao Wu, Di Zhou, Xingyu Tong, Bide Wang, Bingjin Feng, Xiaobo Wang, Kun Song, Yu Yang, Cao Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration |
title | Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration |
title_full | Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration |
title_fullStr | Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration |
title_full_unstemmed | Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration |
title_short | Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration |
title_sort | lysine methylation of ppp1ca by the methyltransferase suv39h2 disrupts tfeb-dependent autophagy and promotes intervertebral disc degeneration |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10482945/ https://www.ncbi.nlm.nih.gov/pubmed/37605006 http://dx.doi.org/10.1038/s41418-023-01210-4 |
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