O-GlcNAcylation mediates the control of cytosolic phosphoenolpyruvate carboxykinase activity via Pgc1a

Latorre, P. (Universidad de Zaragoza) ; Varona, L. (Universidad de Zaragoza) ; Burgos, C. (Universidad de Zaragoza) ; Carrodeguas, J.A. (Universidad de Zaragoza) ; López-Buesa, P. (Universidad de Zaragoza)

Resumen: PGC1a is a coactivator of many transcription factors and cytosolic phosphoenolpyruvate carboxykinase (PCK1) is a key enzyme for gluconeogenesis. PGC1a interacts with the transcription factor PPAR¿ to stimulate PCK1 expression and thus de novo glucose synthesis. These proteins are not only important for central energy metabolism but also for supplying intermediates for other metabolic pathways, including lipidogenesis and protein synthesis and might therefore be important factors in the ethiopathogenesis of metabolic disorders like diabetes but also in other pathologies like cancer. Since polymorphisms in these proteins have been related to some phenotypic traits in animals like pigs and PGC1a G482S polymorphism increases fat deposition in humans, we have investigated the molecular basis of such effects focusing on a commonly studied polymorphism in pig Pgc1a, which changes a cysteine at position 430 (WT) of the protein to a serine (C430S). Biochemical analyses show that Pgc1a WT stimulates higher expression of human PCK1 in HEK293T and HepG2 cells. Paradoxically, Pgc1a WT is less stable than Pgc1a p.C430S in HEK293T cells. However, the study of different post-translational modifications shows a higher O-GlcNAcylation level of Pgc1a p.C430S. This higher O-GlcNAcylation level significantly decreases the interaction between Pgc1a and PPAR¿ demonstrating the importance of post-translational glycosylation of PGC1a in the regulation of PCK1 activity. This, furthermore, could explain at least in part the observed epistatic effects between PGC1a and PCK1 in pigs.

Idioma: Inglés

DOI: 10.1371/journal.pone.0179988

Año: 2017

Publicado en: PloS one 12, 6 (2017), 0179988 [14 pp]
ISSN: 1932-6203

Factor impacto JCR: 2.766 (2017)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 15 / 64 = 0.234 (2017) - Q1 - T1

Factor impacto SCIMAGO: 1.164 - Agricultural and Biological Sciences (miscellaneous) (Q1) - Medicine (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MEC/AGL2015–66177-R
Financiación: info:eu-repo/grantAgreement/ES/UZ/2014-CIE-03
Financiación: info:eu-repo/grantAgreement/ES/UZ/2015-BIO-01

Tipo y forma: Article (Published version)

Área (Departamento): Área Genética (Dpto. Anatom.,Embri.Genét.Ani.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
Área (Departamento): Área Tecnología de Alimentos (Dpto. Produc.Animal Cienc.Ali.)