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1. SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer

Author

Lachiondo-Ortega, Sofia, Rejano-Gordillo, Claudia M., Simon, Jorge, Lopitz-Otsoa, Fernando, C. Delgado, Teresa, Mazan-Mamczarz, Krystyna, Goikoetxea-Usandizaga, Naroa, Zapata-Pavas, L. Estefanía, García-del Río, Ana, Guerra, Pietro, Peña-Sanfélix, Patricia, Hermán-Sánchez, Natalia, Al-Abdulla, Ruba, Fernandez-Rodríguez, Carmen, Azkargorta, Mikel, Velázquez-Cruz, Alejandro, Guyon, Joris, Martín, César, Zalamea, Juan Diego, Egia-Mendikute, Leire, Sanz-Parra, Arantza, Serrano-Maciá, Marina, González-Recio, Irene, Gonzalez-Lopez, Monika, Martínez-Cruz, Luis Alfonso, Pontisso, Patrizia, Aransay, Ana M., Barrio, Rosa, Sutherland, James D., Abrescia, Nicola G.A., Elortza, Félix, Lujambio, Amaia, Banales, Jesus M., Luque, Raúl M., Gahete, Manuel D., Palazón, Asís, Avila, Matias A., G. Marin, Jose J., De, Supriyo, Daubon, Thomas, Díaz-Quintana, Antonio, Díaz-Moreno, Irene, Gorospe, Myriam, Rodríguez, Manuel S., and Martínez-Chantar, María Luz

Published
2024
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3. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

Author

Gonzalez-Rellan, María J., Fernández, Uxía, Parracho, Tamara, Novoa, Eva, Fondevila, Marcos F., da Silva Lima, Natalia, Ramos, Lucía, Rodríguez, Amaia, Serrano-Maciá, Marina, Perez-Mejias, Gonzalo, Chantada-Vazquez, Pilar, Riobello, Cristina, Veyrat-Durebex, Christelle, Tovar, Sulay, Coppari, Roberto, Woodhoo, Ashwin, Schwaninger, Markus, Prevot, Vincent, Delgado, Teresa C., Lopez, Miguel, Diaz-Quintana, Antonio, Dieguez, Carlos, Guallar, Diana, Frühbeck, Gema, Diaz-Moreno, Irene, Bravo, Susana B., Martinez-Chantar, Maria L., and Nogueiras, Ruben

Published
2023
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4. Nucleus-translocated mitochondrial cytochrome c liberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid–liquid phase separation

Author

González-Arzola, Katiuska, Díaz-Quintana, Antonio, Bernardo-García, Noelia, Martínez-Fábregas, Jonathan, Rivero-Rodríguez, Francisco, Casado-Combreras, Miguel Á., Elena-Real, Carlos A., Velázquez-Cruz, Alejandro, Gil-Caballero, Sergio, Velázquez-Campoy, Adrián, Szulc, Elzbieta, Gavilán, María P., Ayala, Isabel, Arranz, Rocío, Ríos, Rosa M., Salvatella, Xavier, Valpuesta, José M., Hermoso, Juan A., De la Rosa, Miguel A., and Díaz-Moreno, Irene

Published
2022
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9. SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia e Innovación (MICIN). España, Instituto de Salud Carlos III, Fundación la Caixa, Consejo Nacional de Ciencia y Tecnología (CONACYT). México, European Union (UE), National Institutes of Health. United States, Junta de Andalucía, Junta de Castilla-León, Gobierno de Navarra, Gobierno Vasco, National Cancer Institute (NCI), NIH. United States, Lachiondo Ortega, Sofia, Rejano Gordillo, Claudia M., Simon, Jorge, Lopitz Otsoa, Fernando, C. Delgado, Teresa, Mazan Mamczarz, Krystyna, Goikoetxea Usandizaga, Naroa, Velázquez Cruz, Alejandro, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, Martínez-Chantar, María Luz, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia e Innovación (MICIN). España, Instituto de Salud Carlos III, Fundación la Caixa, Consejo Nacional de Ciencia y Tecnología (CONACYT). México, European Union (UE), National Institutes of Health. United States, Junta de Andalucía, Junta de Castilla-León, Gobierno de Navarra, Gobierno Vasco, National Cancer Institute (NCI), NIH. United States, Lachiondo Ortega, Sofia, Rejano Gordillo, Claudia M., Simon, Jorge, Lopitz Otsoa, Fernando, C. Delgado, Teresa, Mazan Mamczarz, Krystyna, Goikoetxea Usandizaga, Naroa, Velázquez Cruz, Alejandro, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, and Martínez-Chantar, María Luz

Abstract

The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.

Published
2024

10. Mitochondrial Factors in the Cell Nucleus

Author

Junta de Andalucía, González-Arzola, Katiuska [0000-0002-1124-3847], Díaz-Quintana, Antonio [0000-0001-8973-8009], González-Arzola, Katiuska, Díaz-Quintana, Antonio, Junta de Andalucía, González-Arzola, Katiuska [0000-0002-1124-3847], Díaz-Quintana, Antonio [0000-0001-8973-8009], González-Arzola, Katiuska, and Díaz-Quintana, Antonio

Abstract

The origin of eukaryotic organisms involved the integration of mitochondria into the ancestor cell, with a massive gene transfer from the original proteobacterium to the host nucleus. Thus, mitochondrial performance relies on a mosaic of nuclear gene products from a variety of genomes. The concerted regulation of their synthesis is necessary for metabolic housekeeping and stress response. This governance involves crosstalk between mitochondrial, cytoplasmic, and nuclear factors. While anterograde and retrograde regulation preserve mitochondrial homeostasis, the mitochondria can modulate a wide set of nuclear genes in response to an extensive variety of conditions, whose response mechanisms often merge. In this review, we summarise how mitochondrial metabolites and proteins-encoded either in the nucleus or in the organelle-target the cell nucleus and exert different actions modulating gene expression and the chromatin state, or even causing DNA fragmentation in response to common stress conditions, such as hypoxia, oxidative stress, unfolded protein stress, and DNA damage.

Published
2023

13. Nucleus-translocated mitochondrial cytochrome c liberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid-liquid phase separation

Author

Universidad de Sevilla, ALBA Synchrotron, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Junta de Andalucía, European Commission, Fundación Ramón Areces, Ministerio de Educación, Cultura y Deporte (España), Fundación la Caixa, Fundación Científica Asociación Española Contra el Cáncer, González-Arzola, Katiuska [0000-0002-1124-3847], Díaz-Quintana, Antonio [0000-0001-8973-8009], Martínez-Fábregas, Jonathan [0000-0001-5809-065X], Casado-Combreras, Miguel Á. [0000-0003-3375-7758], Velázquez-Cruz, Alejandro [0000-0002-4589-0989], Velázquez-Campoy, Adrián [0000-0001-5702-4538], Gavilán, María P. [0000-0003-3694-8525], Arranz, Rocío [0000-0001-5321-0915], Salvatella, Xavier [0000-0002-8371-4185], Valpuesta, José M. [0000-0001-7468-8053], Hermoso, Juan A. [0000-0002-1862-8950], Rosa, Miguel A. de la [0000-0003-1187-5737], Díaz-Moreno, Irene [0000-0002-5318-7644], González-Arzola, Katiuska, Díaz-Quintana, Antonio, Bernardo-García, Noelia, Martínez-Fábregas, Jonathan, Rivero-Rodríguez, Francisco, Casado-Combreras, Miguel Á., Elena-Real, Carlos A., Velázquez-Cruz, Alejandro, Gil-Caballero, Sergio, Velázquez-Campoy, Adrián, Szulc, Elzbieta, Gavilán, María P., Ayala, Isabel, Arranz, Rocío, Ríos, Rosa M., Salvatella, Xavier, Valpuesta, José M., Hermoso, Juan A., Rosa, Miguel A. de la, Díaz-Moreno, Irene, Universidad de Sevilla, ALBA Synchrotron, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Junta de Andalucía, European Commission, Fundación Ramón Areces, Ministerio de Educación, Cultura y Deporte (España), Fundación la Caixa, Fundación Científica Asociación Española Contra el Cáncer, González-Arzola, Katiuska [0000-0002-1124-3847], Díaz-Quintana, Antonio [0000-0001-8973-8009], Martínez-Fábregas, Jonathan [0000-0001-5809-065X], Casado-Combreras, Miguel Á. [0000-0003-3375-7758], Velázquez-Cruz, Alejandro [0000-0002-4589-0989], Velázquez-Campoy, Adrián [0000-0001-5702-4538], Gavilán, María P. [0000-0003-3694-8525], Arranz, Rocío [0000-0001-5321-0915], Salvatella, Xavier [0000-0002-8371-4185], Valpuesta, José M. [0000-0001-7468-8053], Hermoso, Juan A. [0000-0002-1862-8950], Rosa, Miguel A. de la [0000-0003-1187-5737], Díaz-Moreno, Irene [0000-0002-5318-7644], González-Arzola, Katiuska, Díaz-Quintana, Antonio, Bernardo-García, Noelia, Martínez-Fábregas, Jonathan, Rivero-Rodríguez, Francisco, Casado-Combreras, Miguel Á., Elena-Real, Carlos A., Velázquez-Cruz, Alejandro, Gil-Caballero, Sergio, Velázquez-Campoy, Adrián, Szulc, Elzbieta, Gavilán, María P., Ayala, Isabel, Arranz, Rocío, Ríos, Rosa M., Salvatella, Xavier, Valpuesta, José M., Hermoso, Juan A., Rosa, Miguel A. de la, and Díaz-Moreno, Irene

Abstract

The regular functioning of the nucleolus and nucleus-mitochondria crosstalk are considered unrelated processes, yet cytochrome c (Cc) migrates to the nucleus and even the nucleolus under stress conditions. Nucleolar liquid-liquid phase separation usually serves the cell as a fast, smart mechanism to control the spatial localization and trafficking of nuclear proteins. Actually, the alternative reading frame (ARF), a tumor suppressor protein sequestered by nucleophosmin (NPM) in the nucleoli, is shifted out from NPM upon DNA damage. DNA damage also triggers early translocation of respiratory Cc to nucleus before cytoplasmic caspase activation. Here, we show that Cc can bind to nucleolar NPM by triggering an extended-to-compact conformational change, driving ARF release. Such a NPM-Cc nucleolar interaction can be extended to a general mechanism for DNA damage in which the lysine-rich regions of Cc-rather than the canonical, arginine-rich stretches of membrane-less organelle components-controls the trafficking and availability of nucleolar proteins.

Published
2022

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Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Educación y Cultura (MEC). España, European Commission. Fondo Social Europeo (FSO), European Molecular Biology Organization (EMBO), European ARBRE-Mobieu consortium (COST Action), Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Buzón, Pedro, Velázquez Cruz, Alejandro, Corrales Guerrero, Laura, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, Roos, Wouter H., Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Educación y Cultura (MEC). España, European Commission. Fondo Social Europeo (FSO), European Molecular Biology Organization (EMBO), European ARBRE-Mobieu consortium (COST Action), Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Buzón, Pedro, Velázquez Cruz, Alejandro, Corrales Guerrero, Laura, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, and Roos, Wouter H.

Published
2023

15. Mitochondrial Factors in the Cell Nucleus

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Junta de Andalucía, González Arzola, Katiuska, Díaz Quintana, Antonio Jesús, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Junta de Andalucía, González Arzola, Katiuska, and Díaz Quintana, Antonio Jesús

Abstract

The origin of eukaryotic organisms involved the integration of mitochondria into the ancestor cell, with a massive gene transfer from the original proteobacterium to the host nucleus. Thus, mitochondrial performance relies on a mosaic of nuclear gene products from a variety of genomes. The concerted regulation of their synthesis is necessary for metabolic housekeeping and stress response. This governance involves crosstalk between mitochondrial, cytoplasmic, and nuclear factors. While anterograde and retrograde regulation preserve mitochondrial homeostasis, the mitochondria can modulate a wide set of nuclear genes in response to an extensive variety of conditions, whose response mechanisms often merge. In this review, we summarise how mitochondrial metabolites and proteins—encoded either in the nucleus or in the organelle—target the cell nucleus and exert different actions modulating gene expression and the chromatin state, or even causing DNA fragmentation in response to common stress conditions, such as hypoxia, oxidative stress, unfolded protein stress, and DNA damage.

Published
2023

16. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Xunta de Galicia, European Community (EC), González Rellán, María J., Fernández, Uxía, Parracho, Tamara, Novoa, Eva, Fondevila, Marcos F., Da Silva Lima, Natalia, Rodríguez, Amaia, Pérez Mejías, Gonzalo, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, Nogueiras, Rubén, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Xunta de Galicia, European Community (EC), González Rellán, María J., Fernández, Uxía, Parracho, Tamara, Novoa, Eva, Fondevila, Marcos F., Da Silva Lima, Natalia, Rodríguez, Amaia, Pérez Mejías, Gonzalo, Díaz Quintana, Antonio Jesús, Díaz Moreno, Irene, and Nogueiras, Rubén

Abstract

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.

Published
2023

17. Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Principado de Asturias, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (CSIC), Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Fundación la Caixa, Gobierno Vasco, Roberti, Annalisa, Tejedor, Juan Ramón, Díaz Moreno, Irene, López, Virginia, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Urdinguio, Rocío G., Concellón, Carmen, Martínez-Chantar, María Luz, Fernández Morera, Juan Luis, Díaz Quintana, Antonio Jesús, Amo, Vicente del, Fernández, Agustín F., Fraga, Mario F., Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Principado de Asturias, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (CSIC), Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Fundación la Caixa, Gobierno Vasco, Roberti, Annalisa, Tejedor, Juan Ramón, Díaz Moreno, Irene, López, Virginia, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Urdinguio, Rocío G., Concellón, Carmen, Martínez-Chantar, María Luz, Fernández Morera, Juan Luis, Díaz Quintana, Antonio Jesús, Amo, Vicente del, Fernández, Agustín F., and Fraga, Mario F.

Abstract

Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of transcriptional events coordinates the differentiation of pre-adipocytes into fully differentiated adipocytes; the process of adipogenesis. Although nicotinamide N-methyltransferase (NNMT) has been associated with obesity, how NNMT is regulated during adipogenesis, and the underlying regulatory mechanisms, remain undefined. In present study we used genetic and pharmacological approaches to elucidate the molecular signals driving NNMT activation and its role during adipogenesis. Firstly, we demonstrated that during the early phase of adipocyte differentiation NNMT is transactivated by CCAAT/Enhancer Binding Protein beta (CEBPB) in response to glucocorticoid (GC) induction. We found that Nnmt knockout, using CRISPR/Cas9 approach, impaired terminal adipogenesis by influencing the timing of cellular commitment and cell cycle exit during mitotic clonal expansion, as demonstrated by cell cycle analysis and RNA sequencing experiments. Biochemical and computational methods showed that a novel small molecule, called CC-410, stably binds to and highly specifically inhibits NNMT. CC-410 was, therefore, used to modulate protein activity during pre-adipocyte differentiation stages, demonstrating that, in line with the genetic approach, chemical inhibition of NNMT at the early stages of adipogenesis impairs terminal differentiation by deregulating the GC network. These congruent results conclusively demonstrate that NNMT is a key component of the GC-CEBP axis during the early stages of adipogenesis and could be a potential therapeutic target for both early-onset obesity and glucocorticoid-induced obesity.

Published
2023

18. Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis

Author

Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Fundación General CSIC, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundación Ramón Areces, Junta de Andalucía, Fundación la Caixa, Consejo Superior de Investigaciones Científicas (España), Instituto Universitario de Oncología del Principado de Asturias, Eusko Jaurlaritza, Liberbank, Obra Social Cajastur, Ministerio de Economía y Competitividad (España), Roberti, Annalisa, Tejedor, Juan Ramón, Díaz-Moreno, Irene, López, Virginia, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Urdinguio, Rocío G., Concellón, Carmen, Martínez-Chantar, María Luz, Fernández-Morera, Juan L., Díaz-Quintana, Antonio, Amo, Vicente del, Fernández, Agustín F., Fraga, Mario F., Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Fundación General CSIC, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundación Ramón Areces, Junta de Andalucía, Fundación la Caixa, Consejo Superior de Investigaciones Científicas (España), Instituto Universitario de Oncología del Principado de Asturias, Eusko Jaurlaritza, Liberbank, Obra Social Cajastur, Ministerio de Economía y Competitividad (España), Roberti, Annalisa, Tejedor, Juan Ramón, Díaz-Moreno, Irene, López, Virginia, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Urdinguio, Rocío G., Concellón, Carmen, Martínez-Chantar, María Luz, Fernández-Morera, Juan L., Díaz-Quintana, Antonio, Amo, Vicente del, Fernández, Agustín F., and Fraga, Mario F.

Abstract

Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of transcriptional events coordinates the differentiation of pre-adipocytes into fully differentiated adipocytes; the process of adipogenesis. Although nicotinamide N-methyltransferase (NNMT) has been associated with obesity, how NNMT is regulated during adipogenesis, and the underlying regulatory mechanisms, remain undefined. In present study we used genetic and pharmacological approaches to elucidate the molecular signals driving NNMT activation and its role during adipogenesis. Firstly, we demonstrated that during the early phase of adipocyte differentiation NNMT is transactivated by CCAAT/Enhancer Binding Protein beta (CEBPB) in response to glucocorticoid (GC) induction. We found that Nnmt knockout, using CRISPR/Cas9 approach, impaired terminal adipogenesis by influencing the timing of cellular commitment and cell cycle exit during mitotic clonal expansion, as demonstrated by cell cycle analysis and RNA sequencing experiments. Biochemical and computational methods showed that a novel small molecule, called CC-410, stably binds to and highly specifically inhibits NNMT. CC-410 was, therefore, used to modulate protein activity during pre-adipocyte differentiation stages, demonstrating that, in line with the genetic approach, chemical inhibition of NNMT at the early stages of adipogenesis impairs terminal differentiation by deregulating the GC network. These congruent results conclusively demonstrate that NNMT is a key component of the GC-CEBP axis during the early stages of adipogenesis and could be a potential therapeutic target for both early-onset obesity and glucocorticoid-induced obesity.

Published
2023

19. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology

Author

Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, Universidad de Sevilla, Fundación Ramón Areces, Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, Zoledziewska, Magdalena, Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, Universidad de Sevilla, Fundación Ramón Areces, Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, and Zoledziewska, Magdalena

Abstract

Few genome-wide association studies (GWAS) analyzing genetic regulation of morphological traits of white blood cells have been reported. We carried out a GWAS of 12 morphological traits in 869 individuals from the general population of Sardinia, Italy. These traits, included measures of cell volume, conductivity and light scatter in four white-cell populations (eosinophils, lymphocytes, monocytes, neutrophils). This analysis yielded seven statistically significant signals, four of which were novel (four novel, PRG2, P2RX3, two of CDK6). Five signals were replicated in the independent INTERVAL cohort of 11 822 individuals. The most interesting signal with large effect size on eosinophil scatter (P-value = 8.33 x 10-32, beta = -1.651, se = 0.1351) falls within the innate immunity cluster on chromosome 11, and is located in the PRG2 gene. Computational analyses revealed that a rare, Sardinian-specific PRG2:p.Ser148Pro mutation modifies PRG2 amino acid contacts and protein dynamics in a manner that could possibly explain the changes observed in eosinophil morphology. Our discoveries shed light on genetics of morphological traits. For the first time, we describe such large effect size on eosinophils morphology that is relatively frequent in Sardinian population.

Published
2023

20. Phosphorylation disrupts long-distance electron transport in cytochrome c

Author

Gomila, Alexandre, primary, Pérez-Mejías, Gonzalo, additional, Hill, Alba Nin, additional, Guerra, Alejandra, additional, Casas-Ferrer, Laura, additional, Ortiz-Tescari, Sthefany, additional, Díaz-Quintana, Antonio, additional, Samitier, Josep, additional, Rovira, Carme, additional, Rosa, Miguel A. De la, additional, Díaz-Moreno, Irene, additional, Gorostiza, Pau, additional, Giannotti, Marina, additional, and Lagunas, Anna, additional

Published
2022
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21. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology

Author

Marongiu, Michele, primary, Pérez-Mejías, Gonzalo, additional, Orrù, Valeria, additional, Steri, Maristella, additional, Sidore, Carlo, additional, Díaz-Quintana, Antonio, additional, Mulas, Antonella, additional, Busonero, Fabio, additional, Maschio, Andrea, additional, Walter, Klaudia, additional, Tardaguila, Manuel, additional, Akbari, Parsa, additional, Soranzo, Nicole, additional, Fiorillo, Edoardo, additional, Gorospe, Myriam, additional, Schlessinger, David, additional, Díaz-Moreno, Irene, additional, Cucca, Francesco, additional, and Zoledziewska, Magdalena, additional

Published
2022
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22. Nucleus-translocated mitochondrial cytochrome c liberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid-liquid phase separation.

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Gobierno de España, Ministerio de Ciencia e Innovación (MICIN). España, Agencia Estatal de Investigación. España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Junta de Andalucía, González Arzola, Katiuska, Díaz Quintana, Antonio Jesús, Bernardo García, Noelia, Martínez Fábregas, Jonathan, Rivero Rodríguez, Francisco, Casado Combreras, Miguel Ángel, Elena-Real, Carlos A., Velázquez Cruz, Alejandro, Gil Caballero, Sergio, Velázquez Campoy, Adrián, Szulc, Elzbieta, Gavilán Dorronzoro, María de la Paz, Ayala, Isabel, Arranz, Rocío, Ríos, Rosa M., Salvatella, Xavier, Valpuesta, José María, Hermoso, Juan A., Rosa Acosta, Miguel Ángel de la, Díaz Moreno, Irene, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Gobierno de España, Ministerio de Ciencia e Innovación (MICIN). España, Agencia Estatal de Investigación. España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Junta de Andalucía, González Arzola, Katiuska, Díaz Quintana, Antonio Jesús, Bernardo García, Noelia, Martínez Fábregas, Jonathan, Rivero Rodríguez, Francisco, Casado Combreras, Miguel Ángel, Elena-Real, Carlos A., Velázquez Cruz, Alejandro, Gil Caballero, Sergio, Velázquez Campoy, Adrián, Szulc, Elzbieta, Gavilán Dorronzoro, María de la Paz, Ayala, Isabel, Arranz, Rocío, Ríos, Rosa M., Salvatella, Xavier, Valpuesta, José María, Hermoso, Juan A., Rosa Acosta, Miguel Ángel de la, and Díaz Moreno, Irene

Abstract

The regular functioning of the nucleolus and nucleus-mitochondria crosstalk are considered unrelated processes, yet cytochrome c (Cc) migrates to the nucleus and even the nucleolus under stress conditions. Nucleolar liquid–liquid phase separation usually serves the cell as a fast, smart mechanism to control the spatial localization and trafcking of nuclear proteins. Actually, the alternative reading frame (ARF), a tumor suppressor protein sequestered by nucleophosmin (NPM) in the nucleoli, is shifted out from NPM upon DNA damage. DNA damage also triggers early translocation of respiratory Cc to nucleus before cytoplasmic caspase activation. Here, we show that Cc can bind to nucleolar NPM by triggering an extended-to-compact conformational change, driving ARF release. Such a NPM–Cc nucleolar interaction can be extended to a general mechanism for DNA damage in which the lysine-rich regions of Cc—rather than the canonical, arginine-rich stretches of membrane-less organelle components—controls the trafcking and availability of nucleolar proteins.

Published
2022

23. Phosphorylation disrupts long-distance electron transport in cytochrome c

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, European Union (UE), Ministerio de Ciencia e Innovación (MICIN). España, Generalitat de Catalunya, Junta de Andalucía, Gomila, Alexandre M.J., Pérez Mejías, Gonzalo, Nin-Hill, Alba, Guerra Castellano, Alejandra, Casas Ferrer, Laura, Ortiz Tescari, Sthefany, Díaz Quintana, Antonio Jesús, Samitier, Josep, Rovira, Carme, Rosa Acosta, Miguel Ángel de la, Díaz Moreno, Irene, Gorostiza, Pau, Giannotti, Marina I., Lagunas, Anna, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, European Union (UE), Ministerio de Ciencia e Innovación (MICIN). España, Generalitat de Catalunya, Junta de Andalucía, Gomila, Alexandre M.J., Pérez Mejías, Gonzalo, Nin-Hill, Alba, Guerra Castellano, Alejandra, Casas Ferrer, Laura, Ortiz Tescari, Sthefany, Díaz Quintana, Antonio Jesús, Samitier, Josep, Rovira, Carme, Rosa Acosta, Miguel Ángel de la, Díaz Moreno, Irene, Gorostiza, Pau, Giannotti, Marina I., and Lagunas, Anna

Abstract

t has been recently shown that electron transfer between mitochondrial cytochrome c and the cytochrome c1 subunit of the cytochrome bc1 can proceed at long-distance through the aqueous solution. Cytochrome c is thought to adjust its activity by changing the affinity for its partners via Tyr48 phosphorylation, but it is unknown how it impacts the nanoscopic environment, interaction forces, and long-range electron transfer. Here, we constrain the orientation and separation between cytochrome c1 and cytochrome c or the phosphomimetic Y48pCMF cytochrome c, and deploy an array of single-molecule, bulk, and computational methods to investigate the molecular mechanism of electron transfer regulation by cytochrome c phosphorylation. We demonstrate that phosphorylation impairs long-range electron transfer, shortens the long-distance charge conduit between the partners, strengthens their interaction, and departs it from equilibrium. These results unveil a nanoscopic view of the interaction between redox protein partners in electron transport chains and its mechanisms of regulation.

Published
2022

24. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology.

Author

Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, and Zoledziewska, Magdalena

Published
2023
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25. Nucleus-translocated mitochondrial cytochrome cliberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid–liquid phase separation

Author

González-Arzola, Katiuska, Díaz-Quintana, Antonio, Bernardo-García, Noelia, Martínez-Fábregas, Jonathan, Rivero-Rodríguez, Francisco, Casado-Combreras, Miguel Á., Elena-Real, Carlos A., Velázquez-Cruz, Alejandro, Gil-Caballero, Sergio, Velázquez-Campoy, Adrián, Szulc, Elzbieta, Gavilán, María P., Ayala, Isabel, Arranz, Rocío, Ríos, Rosa M., Salvatella, Xavier, Valpuesta, José M., Hermoso, Juan A., De la Rosa, Miguel A., and Díaz-Moreno, Irene

Abstract

The regular functioning of the nucleolus and nucleus-mitochondria crosstalk are considered unrelated processes, yet cytochrome c(Cc) migrates to the nucleus and even the nucleolus under stress conditions. Nucleolar liquid–liquid phase separation usually serves the cell as a fast, smart mechanism to control the spatial localization and trafficking of nuclear proteins. Actually, the alternative reading frame (ARF), a tumor suppressor protein sequestered by nucleophosmin (NPM) in the nucleoli, is shifted out from NPM upon DNA damage. DNA damage also triggers early translocation of respiratory Ccto nucleus before cytoplasmic caspase activation. Here, we show that Cccan bind to nucleolar NPM by triggering an extended-to-compact conformational change, driving ARF release. Such a NPM–Ccnucleolar interaction can be extended to a general mechanism for DNA damage in which the lysine-rich regions of Cc—rather than the canonical, arginine-rich stretches of membrane-less organelle components—controls the trafficking and availability of nucleolar proteins.

Published
2022
Full Text
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27. Modulatory effects of CNNM4 on protein- l -isoaspartyl- O -methyltransferase repair function during alcohol-induced hepatic damage.

Author

González-Recio I, Goikoetxea-Usandizaga N, Rejano-Gordillo CM, Conter C, Rodríguez Agudo R, Serrano-Maciá M, Zapata-Pavas LE, Peña-Sanfélix P, Azkargorta M, Elortza F, Herranz JM, Guillamon Thiery Á, Guerra-Ruiz AR, Jover R, Galicia-Garcia U, Martín C, Schaeper U, Delgado TC, Díaz-Moreno I, Díaz Quintana A, Buccella D, Nogueiras R, Argemi J, Ávila MA, Gratacós-Ginès J, Iruzubieta P, Pose E, Bataller R, Crespo J, Martínez-Cruz LA, and Martínez-Chantar ML

Abstract

Background and Aims: Alcohol-associated liver disease (ALD) is a leading cause of liver-related mortality worldwide, with limited treatment options beyond abstinence and liver transplantation. Chronic alcohol consumption has been linked to magnesium (Mg 2+ ) deficiency, which can influence liver disease progression. The mechanisms underlying Mg 2+ homeostasis dysregulation in ALD remain elusive. This study aimed to investigate the role of the Mg 2+ transporter Cyclin M4 (CNNM4) in ALD by analyzing its expression patterns in patients with ALD and preclinical animal models., Approach and Results: In this study, CNNM4 is upregulated in the liver of both patients with ALD and animal models. CNNM4 overexpression triggers Mg 2+ homeostasis dysregulation, linked to ALD progression. We propose a novel therapeutic approach for ALD treatment using N -acetylgalactosamine silencing RNA technology to specifically modulate Cnnm4 expression in the liver, improving mitochondrial function and alleviating endoplasmic reticulum stress. Notably, silencing Cnnm4 restores protein isoaspartyl methyltransferase (PCMT1) activity, essential for repairing ethanol-induced protein damage. Enhancing mitochondrial activity through Cnnm4-dependent mechanisms increases S -adenosylmethionine levels, crucial for PCMT1 function, highlighting the interconnected roles of mitochondrial health and protein homeostasis in ALD treatment., Conclusions: These findings shed light on the dysregulation of Mg 2+ homeostasis in ALD, providing a promising therapeutic approach targeting CNNM4. N -acetylgalactosamine si Cnnm4 therapy boosts the repair processes of ethanol-damaged proteins through the upregulation of PCMT1 activity., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Published
2024
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