Díaz-Quintana, A. (Antonio)

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    Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism
    (Elsevier, 2023) Tovar, S. (Sulay); Nogueiras, R. (Rubén); Díaz-Quintana, A. (Antonio); Pérez-Mejias, G. (Gonzalo); Bravo, S. (Susana B.); Fernández, U. (Uxía); Gonzalez-Rellan, M.J. (María J.); Fondevila, M.F. (Marcos F.); Coppari, R. (Roberto); Veyrat-Durebex, C. (Christelle); Parracho, T. (Tamara); Woodhoo, A. (Ashwin); Frühbeck, G. (Gema); Novoa, E. (Eva); Prevot, V. (Vincent); da-Silva-Lima, N. (Natalia); Dieguez, C. (Carlos); Delgado, T.C. (Teresa C.); Rodriguez, A. (Amaia); Guallar, D. (Diana); Schwaninger, M. (Markus); López, M. (Miguel); Ramos, L. (Lucía); Chantada-Vazquez, P. (Pilar); Díaz-Moreno, I. (Irene); Martinez-Chantar, M.L. (María Luz); Riobello, C; Serrano-Macia, M. (Marina)
    Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
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    SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer
    (Elsevier BV, 2019) Villa, E. (Erica); Simon, J. (Jorge); Carlevaris, O. (Onintza); Gutiérrez-de-Juan, V. (Virginia); Díaz-Quintana, A. (Antonio); García-Rodríguez, J.L. (Juan L.); Zubiete-Franco, I. (Imanol); Avila, M.A. (Matías Antonio); Martín, C. (Cesar); Beraza, N. (Naiara); Rodriguez, M. (Manuel); Beguiristain-Gómez, A. (Adolfo); Varela-Rey, M. (Marta); Delgado, T.C. (Teresa C.); Barbier-Torres, L. (Lucía); López-de-Davalillo, S. (Sergio); Lopitz-Otsoa, F. (Fernando); Fernández-Ramos, D. (David); Berra, E. (Edurne); Fernández-Tussy, P. (Pablo); Mato, J.M. (José María); Aspichueta, P. (Patricia); Díaz-Moreno, I. (Irene); Martinez-Chantar, M.L. (María Luz); Calvisi, D.F. (Diego F.); Serrano-Macia, M. (Marina)
    Background: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC). Methods: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC. Findings: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using sitedirected mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors. Interpretation: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer.