Reference

Latorre-Muro, P., Baeza, J., Armstrong, E. A., Hurtado-Guerrero, R., Corzana, F., Wu, L.E., Sinclair, D.A., López-Buesa, P., Carrodeguas, J.A., Denu, J.M. (2018). Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions. Mol. Cell 71, 718-732. doi: 10.1016/j.molcel.2018.07.031. Portada MOL CELL

Authors

Latorre-Muro, Pedro, Baeza, Josue, Armstrong, Eric A., Hurtado-Guerrero, Ramón, Corzana, Francisco, Wu, Lindsay E., Sinclair, David A., López-Buesa, Pascual, Carrodeguas, José A., Denu, John M.

Abstract

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 GSK3β-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 hyperacetylated PCK1 to promote anaplerotic activity, and the intersection of post-translational control of PCK1 involving acetylation, phosphorylation, and ubiquitination.

Description

La fosfoenolpiruvato carboxiquinasa citosólica (PCK1) se encuentra en un cruce de camino de numerosas rutas metabólicas y cataliza una reacción reversible. El papel biológico de PCK1 ha estado asociado al de la gluconeogénesis (una de las reacciones), sin embargo, el papel de la reacción reversa en mamíferos es desconocido. Latorre y cols. describen los mecanismos por los que diversas modificaciones post-traduccionales (PTMs) son capaces de regular tanto la actividad como la estabilidad de la PCK1. En condiciones de alta glucosa, la acetilación de PCK1 favorece la reacción reversa de la enzima que permite suministrar metabolitos al ciclo de Krebs. En estas mismas condiciones, la fosforilación de PCK1 es mediada por GSK3β y favorece la ubiquitinación y degradación de la enzima no acetilada. Por otro lado, en condiciones de baja glucosa, SIRT1 deacetila PCK1 y restaura las propiedades cinéticas de la enzima favoreciendo la ruta gluconeogénica. Esta reacción de deacetilación se ve facilitada por la fosforilación de ciertos residuos. En conjunto, la acetilación, fosforilación y ubiquitinación de PCK1 interactúan con el fin de controlar la estabilidad y el sentido de la reacción de la enzima en función de las condiciones energéticas de las células.

 

 

Latorre Carrodeguas

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de investigación se formó al regresar a España el Dr. Carrodeguas como investigador Ramón y Cajal. Inicialmente dedicado a la biología molecular de la mitocondria, trabajó en líneas de investigación sobre Alzheimer, apoptosis, células madre y metabolismo. En éste último campo realizó estudios con el Dr. López Buesa relacionados con la producción animal. De ahí surgió la semilla de este trabajo, que se consolidó gracias a una estancia del Dr. Latorre Muro en el Wisconsin Institute for Discovery con el Dr. John Denu, completándose en el Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) de la Universidad de Zaragoza.

 Descargar el artículo 

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Read more

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Read more

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements

01-05-2019

/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Read more

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Read more

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Read more

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Read more

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

02-01-2019

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of...

Read more

Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions

01-12-2018

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...

Read more

The Helicase PIF1 Facilitates Resection overSequences Prone to Forming G4 Structures

02-11-2018

DNA breaks are complex lesions that can be repaired either by non-homologous end joining (NHEJ) or by homologous recombination (HR). The decision between these two routes of DNA repair is...

Read more

Preventing loss of mechanosensation by the nuclear membranes of alveolar cells reduces lung injury in mice during mechanical ventilation

01-10-2018

The nuclear membrane acts as a mechanosensor that drives cellular responses following changes in the extracellular environment. Mechanically ventilated lungs are exposed to an abnormally high mechanical load that may...

Read more

Protector Members