Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Toggles Enzyme Activity between Gluconeogenic and Anaplerotic Reactions

Latorre-Muro, Pedro (Universidad de Zaragoza) ; Baeza, J. ; Armstrong, E.A. ; Hurtado-Guerrero, Ramón (Universidad de Zaragoza) ; Corzana, F. ; Wu, L.E. ; Sinclair, D.A. ; López-Buesa, Pascual (Universidad de Zaragoza) ; Carrodeguas, José A. (Universidad de Zaragoza) ; Denu, J.M.

Resumen: Cytosolic phosphoenolpyruvate carboxykinase (PCK1) is considered a gluconeogenic enzyme; however, its metabolic functions and regulatory mechanisms beyond gluconeogenesis are poorly understood. Here, we describe that dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities. Under high glucose, p300-dependent hyperacetylation of PCK1 did not lead to protein degradation but instead increased the ability of PCK1 to perform the anaplerotic reaction, converting phosphoenolpyruvate to oxaloacetate. Lys91 acetylation destabilizes the active site of PCK1 and favors the reverse reaction. At low energy input, we demonstrate that SIRT1 deacetylates PCK1 and fully restores the gluconeogenic ability of PCK1. Additionally, we found that GSK3 beta-mediated phosphorylation of PCK1 decreases acetylation and increases ubiquitination. Biochemical evidence suggests that serine phosphorylation adjacent to Lys91 stimulates SIRT1-dependent deacetylation of PCK1. This work reveals an unexpected capacity of hyper-acetylated PCK1 to promote anaplerotic activity, and the intersection of post-translational control of PCK1 involving acetylation, phosphorylation, and ubiquitination.

Idioma: Inglés

DOI: 10.1016/j.molcel.2018.07.031

Año: 2018

Publicado en: Molecular Cell 71, 5 (2018), 718-732.e1–e8
ISSN: 1097-2765

Factor impacto JCR: 14.548 (2018)

Categ. JCR: CELL BIOLOGY rank: 11 / 191 = 0.058 (2018) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 6 / 294 = 0.02 (2018) - Q1 - T1

Factor impacto SCIMAGO: 12.076 - Molecular Biology (Q1) - Cell Biology (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MEC/BFU2016-75633-P
Financiación: info:eu-repo/grantAgreement/ES/MEC/CTQ2013-44367-C2-2-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/AGL2015-66177
Financiación: info:eu-repo/grantAgreement/ES/UZ-IBERCAJA-CAI/CM1-16
Financiación: info:eu-repo/grantAgreement/ES/UZ/UZ2014-CIE-03
Financiación: info:eu-repo/grantAgreement/ES/UZ/UZ2015-BIO-01

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
Área (Departamento): Área Tecnología de Alimentos (Dpto. Produc.Animal Cienc.Ali.)