The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality.
Aging (Albany NY)
; 11(4): 1110-1128, 2019 02 20.
Article
em En
| MEDLINE
| ID: mdl-30786262
ABSTRACT
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 PKM1PKM2 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 KBTBD8âErk1/2âAurora A axis, and may also affect other essential processes involved in maintaining oocyte quality.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oócitos
/
Piruvato Quinase
/
Hormônios Tireóideos
/
Proteínas de Transporte
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Sistema de Sinalização das MAP Quinases
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Proteínas Adaptadoras de Transdução de Sinal
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Aurora Quinase A
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Proteínas de Membrana
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Aging (Albany NY)
Assunto da revista:
GERIATRIA
Ano de publicação:
2019
Tipo de documento:
Article