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The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality

Tight control of energy metabolism is essential for normal cell function and organism survival. PKM (pyruvate kinase, muscle) isoforms 1 and 2 originate from alternative splicing of PKM pre-mRNA. They are key enzymes in oxidative phosphorylation and aerobic glycolysis, respectively, and are essentia...

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Autores principales: Li, Yan-Ru, Peng, Rui-Rui, Gao, Wen-Yi, Liu, Peng, Chen, Liang-Jian, Zhang, Xiao-Lan, Zhang, Na-Na, Wang, Yang, Du, Lei, Zhu, Feng-Yu, Wang, Li-Li, Li, Cong-Rong, Zeng, Wen-Tao, Li, Jian-Min, Hu, Fan, Zhang, Dong, Yang, Zhi-Xia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402520/
https://www.ncbi.nlm.nih.gov/pubmed/30786262
http://dx.doi.org/10.18632/aging.101802
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author Li, Yan-Ru
Peng, Rui-Rui
Gao, Wen-Yi
Liu, Peng
Chen, Liang-Jian
Zhang, Xiao-Lan
Zhang, Na-Na
Wang, Yang
Du, Lei
Zhu, Feng-Yu
Wang, Li-Li
Li, Cong-Rong
Zeng, Wen-Tao
Li, Jian-Min
Hu, Fan
Zhang, Dong
Yang, Zhi-Xia
author_facet Li, Yan-Ru
Peng, Rui-Rui
Gao, Wen-Yi
Liu, Peng
Chen, Liang-Jian
Zhang, Xiao-Lan
Zhang, Na-Na
Wang, Yang
Du, Lei
Zhu, Feng-Yu
Wang, Li-Li
Li, Cong-Rong
Zeng, Wen-Tao
Li, Jian-Min
Hu, Fan
Zhang, Dong
Yang, Zhi-Xia
author_sort Li, Yan-Ru
collection PubMed
description Tight control of energy metabolism is essential for normal cell function and organism survival. PKM (pyruvate kinase, muscle) isoforms 1 and 2 originate from alternative splicing of PKM pre-mRNA. They are key enzymes in oxidative phosphorylation and aerobic glycolysis, respectively, and are essential for ATP generation. The PKM1:PKM2 expression ratio changes with development and differentiation, and may also vary under metabolic stress and other conditions. Until now, there have been no reports about the function and regulation of PKM isozymes in oocytes. Here, we demonstrate that PKM1 or PKM2 depletion significantly disrupts ATP levels and mitochondrial integrity, and exacerbates free-radical generation and apoptosis in mouse oocytes. We also show that KBTBD8, a female fertility factor in the KBTBD ubiquitin ligase family, selectively regulates PKM1 levels through a signaling cascade that includes Erk1/2 and Aurora A kinases as intermediates. Finally, using RNA sequencing and protein network analysis, we identify several regulatory proteins that may be govern generation of mature PKM1 mRNA. These results suggest KBTBD8 affects PKM1 levels in oocytes via a KBTBD8→Erk1/2→Aurora A axis, and may also affect other essential processes involved in maintaining oocyte quality.
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spelling pubmed-64025202019-03-11 The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality Li, Yan-Ru Peng, Rui-Rui Gao, Wen-Yi Liu, Peng Chen, Liang-Jian Zhang, Xiao-Lan Zhang, Na-Na Wang, Yang Du, Lei Zhu, Feng-Yu Wang, Li-Li Li, Cong-Rong Zeng, Wen-Tao Li, Jian-Min Hu, Fan Zhang, Dong Yang, Zhi-Xia Aging (Albany NY) Research Paper Tight control of energy metabolism is essential for normal cell function and organism survival. PKM (pyruvate kinase, muscle) isoforms 1 and 2 originate from alternative splicing of PKM pre-mRNA. They are key enzymes in oxidative phosphorylation and aerobic glycolysis, respectively, and are essential for ATP generation. The PKM1:PKM2 expression ratio changes with development and differentiation, and may also vary under metabolic stress and other conditions. Until now, there have been no reports about the function and regulation of PKM isozymes in oocytes. Here, we demonstrate that PKM1 or PKM2 depletion significantly disrupts ATP levels and mitochondrial integrity, and exacerbates free-radical generation and apoptosis in mouse oocytes. We also show that KBTBD8, a female fertility factor in the KBTBD ubiquitin ligase family, selectively regulates PKM1 levels through a signaling cascade that includes Erk1/2 and Aurora A kinases as intermediates. Finally, using RNA sequencing and protein network analysis, we identify several regulatory proteins that may be govern generation of mature PKM1 mRNA. These results suggest KBTBD8 affects PKM1 levels in oocytes via a KBTBD8→Erk1/2→Aurora A axis, and may also affect other essential processes involved in maintaining oocyte quality. Impact Journals 2019-02-20 /pmc/articles/PMC6402520/ /pubmed/30786262 http://dx.doi.org/10.18632/aging.101802 Text en Copyright © 2019 Li et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Li, Yan-Ru
Peng, Rui-Rui
Gao, Wen-Yi
Liu, Peng
Chen, Liang-Jian
Zhang, Xiao-Lan
Zhang, Na-Na
Wang, Yang
Du, Lei
Zhu, Feng-Yu
Wang, Li-Li
Li, Cong-Rong
Zeng, Wen-Tao
Li, Jian-Min
Hu, Fan
Zhang, Dong
Yang, Zhi-Xia
The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality
title The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality
title_full The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality
title_fullStr The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality
title_full_unstemmed The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality
title_short The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality
title_sort ubiquitin ligase kbtbd8 regulates pkm1 levels via erk1/2 and aurora a to ensure oocyte quality
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402520/
https://www.ncbi.nlm.nih.gov/pubmed/30786262
http://dx.doi.org/10.18632/aging.101802
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