Cabecera lazomsalas2019 11 08 CBMSO CSIC UAM

Wednesday, 20th November 2019

Molecular and cellular basis of the physio(patho)logy associated with the expression of intracellular antigens


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José María Izquierdo Juárez

ASciStaff

APublications

 

Research Summary:

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The multifunctional TIA proteins regulate gene expression and many relevant physiopathological events.

    

 

 

 
     
 

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Expression of TIA proteins (isoforms b) suppresses in vivo tumor growth. (A-C) Workflow and plots of progression of tumor size after inoculation of TIA1/TIAR-expressing cells and doxycycline (DOX) treatment. (D) Histological sections and immunohistochemical characterization of xenografts tumors. (E and F) Workflow and plot of progression of tumor size after inoculation of TIAR-expressing cells and doxycycline (DOX) treatment.

 

 

 

 

 

 

 

 

The regulation of the heterogeneity of the transcriptome and proteome is key stage on the way to understand differences in the diversity of proteins observed in organisms of similar genetic complexity. The intracellular antigens TIA1 (T-cell intracellular antigen 1) and TIAR/TIAL1 (TIA1 related/like protein) have been involved in the regulation of gene expression on different aspects of the control of RNA metabolism, such as: i) transcription through its interaction with DNA and RNA polymerase II; ii) alternative splicing of pre-mRNA through the selection of atypical 5' splicing sites; iii) localization, stability and/or translation of eukaryotic mRNAs through the interaction with 5' and 3' untranslatable regions; and iv) modulation of biological programmes for cell survival (inflammation, proliferation, apoptosis, cell stress or infections by viruses). As a consequence, the initial hypothesis -of the work line initiated nine years ago- it is that these proteins may play a fundamental role in controlling gene expression by regulating/modulating the dynamics of human transcriptome and proteome, their expression and function, in order to prevent situations which put aberrant cell viability at risk in patho-physiological situations such as stress-associated responses, tumorigenesis or aging and their related diseases. So today, our objective is to characterize the early and late cellular processes and molecular mechanisms in which TIA proteins participate and how they are involved to regulate/modulate cellular homeostasis via preventing the development and/or progression of deleterious phenotypes. Understanding the regulatory dynamics associated with these intracellular antigens could serve as the basis for identifying future therapeutic targets.


 

Publications:

  • Carrascoso, I., Sánchez-Jiménez, C., Silion, E., Alcalde, J., and Izquierdo, J. M. (2018) A heterologous cell model for studying the role of T-cell intracellular antigen 1 in Welander distal myopathy. Mol. Cell. Biol. doi: 10.1128/MCB.00299-18.
  • Carrascoso, I., Alcalde, J., Sánchez-Jiménez, C., González-Sánchez, P., and Izquierdo, J. M. (2017) T-cell intracellular antigens and Hu antigen R antagonistically modulate mitochondrial activity and dynamics by regulating optic atrophy 1 gene expression. Mol. Cell. Biol. 37, e00174-17.
  • Sánchez-Jiménez, C., Ludeña, M. D. and Izquierdo, J. M. (2015) T-cell intracellular antigens function as tumor suppressor genes. Cell Death Dis. 5, 6:e1669.
  • Sánchez-Jiménez, C. and Izquierdo, J. M. (2015) T-cell intracellular antigens in health and disease. Cell Cycle. 14, 2033-2043.
  • Carrascoso, I., Sánchez-Jiménez, C. and Izquierdo, J. M. (2014) Long-term reduction of T-cell intracellular antigens leads to increased beta-actin expression. Mol. Cancer 13, 90.
  • Carrascoso, I., Sánchez-Jiménez, C. and Izquierdo, J. M. (2014) Genome-wide profiling reveals a role for T-cell intracellular antigens TIA1 and TIAR in the control of translational specificity in HeLa cells. Biochem. J. 461, 43-50.

 

Doctoral theses:

Carmen Sánchez-Jiménez (2014). Caracterización de modelos celulares con pérdida y ganancia de función de las proteínas TIA1 y TIAR. Universidad Autónoma de Madrid. Director: José María Izquierdo Juárez.

 


 

If you are interested in joining our group, please write to: This email address is being protected from spambots. You need JavaScript enabled to view it.

Intracellular Signalling in Inflammatory Processes


Grupo-400

 


María N. Navarro

ASciStaff

APublications

Research summary:

The incidence of inflammatory and autoimmune diseases has increased in the last 30 years, particularly among developed countries. Thus, there is a need for the development of novel therapies to treat these pathologies. Interleukin 23 (IL-23) is a pro-inflammatory cytokine whose excessive production plays a fundamental role in the development of several inflammatory diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and psoriasis. The pathological consequences of excessive IL-23 signalling have been linked to its ability to promote effector functions of distinct populations of T lymphocytes: CD4 helper subset Th17 and the TCRγδ T17γδ. Despite the prominent role described for IL-23 in inflammatory diseases, the precise molecular mechanisms by which IL-23 induces pathogenic functions on T lymphocytes remain largely unknown. Our lab is interested in the characterisation of the signalling network triggered by IL-23 using novel techniques such as large-scale quantitative proteomics and phosphoproteomic approaches to uncover novel mediators of IL-23 actions. The underlying aim of this strategy is the development of novel therapeutic tools based on the interference with intracellular signalling pathways. Currently, we are characterising novel signalling mediators that link IL-23 with processes such as cell migration and metabolism. Our work extends beyond the identification of potential targets, and combines pharmacological and genetic approaches to determine the contribution of specific signalling mediators in murine models of IL-23-mediated inflammatory pathologies.

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Selected publications:

  • Álvarez-Salamero C, Castillo-González R, Navarro MN. Lighting Up T Lymphocyte Signaling with Quantitative Phosphoproteomics. Front Immunol. 2017 Aug 9;8:938. doi: 10.3389/fimmu.2017.00938. eCollection 2017. Review. PubMed PMID: 28848546; PubMed Central PMCID: PMC5552657.
  • Navarro MN, Feijoo-Carnero C, Arandilla AG, Trost M, Cantrell DA. Protein kinase D2 is a digital amplifier of T cell receptor-stimulated diacylglycerol signaling in naïve CD8⁺ T cells. Sci Signal. 2014 Oct 21;7(348):ra99. doi: 10.1126/scisignal.2005477. PubMed PMID: 25336615; PubMed Central PMCID: PMC4768351.
  • Navarro MN, Goebel J, Hukelmann JL, Cantrell DA. Quantitative phosphoproteomics of cytotoxic T cells to reveal protein kinase d 2 regulated networks. Mol Cell Proteomics. 2014 Dec;13(12):3544-57. doi: 10.1074/mcp.M113.037242. Epub 2014 Sep 29. PubMed PMID: 25266776; PubMed Central PMCID: PMC4256504.
  • Navarro MN, Cantrell DA. Serine-threonine kinases in TCR signaling. Nat Immunol. 2014 Sep;15(9):808-14. doi: 10.1038/ni.2941. Review. PubMed PMID: 25137455.
  • Navarro MN, Goebel J, Feijoo-Carnero C, Morrice N, Cantrell DA. Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes. Nat Immunol. 2011 Apr;12(4):352-61. doi: 10.1038/ni.2008. Epub 2011 Mar 13. PubMed PMID: 21399638; PubMed Central PMCID: PMC3110993.

Immunometabolism and Inflammation Laboratory


Grupo-400

 


María Mittelbrunn

ASciStaff

APublications

 

Research Summary:

In the last decades, inflammation has been recognized as an important risk factor in numerous human pathologies. Short-term acute inflammation is auto-regulated and needed to defend the organism from pathogens and preserve tissue homeostasis. Chronic inflammation, however, is characterized by infiltrating inflammatory cells, excess cytokine production and deregulation of cell signaling pathways, and has been associated with many diseases including neurodegenerative, cardiovascular, metabolic bone and muscular. Although the cellular and molecular events involved in response to acute inflammation or tissue damage are well understood, less is known about the causes and molecular mechanisms that mediate systemic chronic inflammation. This type of inflammation doesn´t appear to be caused by typical inflammation instigators, as is the case with infections or damaging agents. Instead, they are induced by tissue malfunction and a progressive loss in tissue homeostasis.

The progressive loss of tissue homeostasis and the accumulation of damaged cells are directly associated with aging. In the majority of age-related diseases, patients exhibit an underlying chronic inflammatory state, characterized by a local infiltration of inflammatory cells, mostly macrophages, and elevated levels of pro-inflammatory circulatory cytokines.

Our group is interested in understanding how chronic inflammation may accelerate the aging process. Specifically, we want to study how immune cell metabolism may act as a therapeutic target in delaying aging and age-associated diseases.

The activation, expansion, differentiation and the regression to homeostasis of immune cells are processes associated with metabolic changes. Following antigen recognition, T cells are activated and initiate a proliferation phase characterized by a metabolic change similar to the Warburg effect described in tumoral cells. This metabolic reprogramming could be advantageous for cells that proliferate rapidly, such as cancerous or immune cells. T-cell differentiation and functional fate could be altered by modulating its metabolism. These results have opened up a new field of research, known as immunometabolism, that studies metabolic regulation in the immune response and is currently considered a promising therapeutic window in cancer and autoimmune disease research.

Our major scientific interest involves studying the role of metabolic regulation in the inflammatory response, and defining how immunometabolism may be used as a therapeutic tool in inflammatory diseases and pathologies associated with aging. To do this, we used a murine model whose Tfam gene is specifically deleted in T-cells. Tfam depletion induces a severe decrease in the amount of mitochondrial DNA in T lymphocytes and collapses the expression of important components within the electron transport chain provoking severe mitochondrial dysfunction, alteration of oxidative phosphorylation (OXPHOS) and a significant decrease in mitochondrial ATP production.

The Tfam mouse model has helped us to identify the role of mitochondrial metabolism in the regulation of T-cell inflammatory response by controlling lysosome function. This novel relationship between mitochondria and the cell degradation system can be exploited as a possible therapeutic window in halting chronic inflammation and preventing human diseases associated with aging.

In summary, our lab uses a multidisciplinary approach to explore immunometabolism as a new therapeutic target against chronic inflammation and aging. We hope this strategy strengthens our understanding and helps us learn about new molecular mechanisms involved in human inflammatory pathologies to improve clinical interventions in age-associated diseases.

 

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Relevant publications:

  • Soto-Heredero G, Baixauli F, and Mittelbrunn M. (2017) Interorganelle Communication between Mitochondria and the Endolysosomal System. Front Cell Dev Biol. Nov 7; 5: 95.
  • Desdín-Micó G, Soto-Heredero G, Mittelbrunn M. (2017) Mitochondrial activity in T cells. Mitochondrion. S1567-7249(17)30192-7.
  • Desdín-Micó G, Mittelbrunn M. (2017) Role of exosomes in the protection of cellular homeostasis. 11(2):127-134.
  • Baixauli F, Acín-Pérez R, Villarroya-Beltrí C, Mazzeo C, Nuñez-Andrade N, Gabandé-Rodriguez E, Ledesma MD, Blázquez A, Martin MA, Falcón-Pérez JM, Redondo JM, Enríquez JA, Mittelbrunn M. (2015) Mitochondrial Respiration Controls Lysosomal Function during Inflammatory T Cell Responses. Cell Metab. 22(3):485-98.
  • Baixauli F, López-Otin C, and Mittelbrunn M. (2014) Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness. Front Immunol. Aug 20;5:403.
  • Mittelbrunn M, Sánchez-Madrid F. (2012) Intercellular communication: diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol. 13(5):328-35.

Tetraspanin-enriched membrane microdomains in extracellular vesicles and cell adhesion and migration


Grupo-400

 


 

 

María Yáñez-Mó

 ASciStaff

APublications

 

 

 

 

Research summary:

Our group is focused on the characterization of tetraspanin-enriched microdomains (TEMs), specialized membrane platforms involved in cell-cell adhesion and migration processes as reviewed in 2009 in Trends in Cell Biology (2009).

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Figure 1: Tetraspanin-enriched microdomains and their functions. It has been demonstrated that TEM-induced clustering or segregation of adhesion receptors and signalling molecules plays a functional role in phenomena related to migration and invasion, intercellular adhesion, membrane fusion events and intracellular trafficking. These phenomena are implicated in several biological processes. From Yáñez-Mó et al., Trends Cell Biol. 2009 Sep;19(9):434-46

We have developed two main lines of research. The first one is devoted to the study of membrane-bound proteases, and how their activity is regulated by their inclusion into TEMs, such as in the case of MT1-MMP/CD151/alpha3beta1 integrin ternary complexes.

A second line of research is devoted to the characterization of tetraspanins intracellular connections. Starting with a high throughput proteomic screen, we thereafter study the relevance of the molecular interactions found, in cellular models for fundamental processes of the biology of the immune system (leukocyte migration, immune synapse formation) or tumor cell motility.

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Figure 2: Protein interaction networks for CD81 and EWI-2 ligands identified in human primary lymphoblast-derived exosomes. A, intracellular ligands of CD81 and EWI-2 were manually clustered into groups according to their function using the IPA analysis program. Symbol size is proportional to the number of peptides identified for each protein in the pull-down assays. B, proportions of proteins in exosomes that were identified as ligands of EWI-2 and CD81 in exosomes. The proportions were calculated on the basis of the number of peptides identified per protein in total exosome lysates. From Perez-Hernandez D, Gutiérrez-Vázquez C, Jorge I, López-Martín S, Ursa A, Sánchez-Madrid F, Vázquez J, Yáñez-Mó M. J Biol Chem. 2013 Apr 26;288(17):11649-61

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Figure 3: Tetraspanins in extracelular vesicle formation and function. Tetraspanins have the capacity to interact with several receptor and signaling molecules at the membrane, organizing specialized tetraspanin-enriched microdomains (TEMs) that may play a role in (A) EV biogenesis, (B) the selection of exosome cargo (proteins and miRNAs), (C) the binding and uptake of exosomes by target cells, or (D) the ability of exosomes to present antigen in the context of an immune response. From Andreu Z and Yáñez-Mó M. Front Immunol. 2014 Sep 16;5:442. doi: 10.3389/fimmu.2014.00442

 

Intracellular connections of tetraspanin-enriched microdomains led us also to the field of extracellular vesicle (EV) research, since tetraspanin proteins are among the most abundant proteins on EV. Extracellular vesicles, including microvesicles, ectosomes, shedding vesicles, microparticles and exosomes, represent a novel mechanism of intercellular communication as vehicles for intercellular transfer of functional membrane and cytosolic proteins, lipids, and RNAs.


 

Relevant publications:

  • Biological properties of extracellular vesicles and their physiological functions. Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, Colás E, Cordeiro-da Silva A, Fais S, Falcon-Perez JM, Ghobrial IM, Giebel B, Gimona M, Graner M, Gursel I, Gursel M, Heegaard NH, Hendrix A, Kierulf P, Kokubun K, Kosanovic M, Kralj-Iglic V, Krämer-Albers EM, Laitinen S, Lässer C, Lener T, Ligeti E, Linē A, Lipps G, Llorente A, Lötvall J, Manček-Keber M, Marcilla A, Mittelbrunn M, Nazarenko I, Nolte-'t Hoen EN, Nyman TA, O'Driscoll L, Olivan M, Oliveira C, Pállinger É, Del Portillo HA, Reventós J, Rigau M, Rohde E, Sammar M, Sánchez-Madrid F, Santarém N, Schallmoser K, Ostenfeld MS, Stoorvogel W, Stukelj R, Van der Grein SG, Vasconcelos MH, Wauben MH, De Wever O.J Extracell Vesicles. 2015 May 14;4:27066. doi: 10.3402/jev.v4.27066. eCollection 2015. PMID: 25979354
  • Tetraspanins in extracellular vesicle formation and function. Andreu Z, Yáñez-Mó M. Front Immunol. 2014 Sep 16;5:442. doi: 10.3389/fimmu.2014.00442. eCollection 2014. Review. PMID: 25278937
  • The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. Perez-Hernandez D, Gutiérrez-Vázquez C, Jorge I, López-Martín S, Ursa A, Sánchez-Madrid F, Vázquez J, Yáñez-Mó M. J Biol Chem. 2013 Apr 26;288(17):11649-61. doi:10.1074/jbc.M112.445304. Epub 2013 Mar 5. PMID: 23463506
  • CD81 regulates cell migration through its association with Rac GTPase. Tejera E, Rocha-Perugini V, López-Martín S, Pérez-Hernández D, Bachir AI, Horwitz AR, Vázquez J, Sánchez-Madrid F, Yáñez-Mo M. Mol Biol Cell. 2013 Feb;24(3):261-73. doi: 10.1091/mbc.E12-09-0642. Epub 2012 Dec 21. PMID: 23264468
  • EWI-2 association with α-actinin regulates T cell immune synapses and HIV viral infection. Gordón-Alonso M, Sala-Valdés M, Rocha-Perugini V, Pérez-Hernández D, López-Martín S, Ursa A, Alvarez S, Kolesnikova TV, Vázquez J, Sánchez-Madrid F, Yáñez-Mó M. J Immunol. 2012 Jul 15;189(2):689-700

Cell biology of inflammation

 

2016 02 Grupo Jaime Millan 400px

 


Jaime Millán

 

 ASciStaff

 

APublications

 

 

 

Research summary:

Inflammation is a primary response to infection, stress and injury. Pathological and chronic inflammation leads to diseases such as atherosclerosis, multiple sclerosis or hepatitis. Long-term inflammatory responses are orchestrated by the secretion of soluble factors that stimulate cells in the surroundings of an inflammatory focus. Among these, the pro inflammatory cytokine TNF is central to inflammation and facilitates the recruitment of immune cells to damaged tissue areas by disrupting cellular barriers. We use TNF as a model cytokine for studying the molecular mechanisms underlying the alteration of cellular barriers during the inflammatory response.

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Reticular endothelial cell-cell junctions composed of PECAM-1 (red), an adhesion receptor involved in leukocyte diapedesis, and VE-cadherin (green).
 endocornea pequeno
The Endocornea project is a collaboration between the Instituto de Investigación Sanitaria Fundación Jiménez Díaz and CSIC to investigate the molecular mechanisms regulating corneal endothelial barrier function and its responses to inflammatory stress.

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Our research interest: Cellular barriers in the lymphocyte journey through the inflamed tissue. Inflammatory cytokines, such as TNF, modulate the integrity of cellular barriers to facilitate the passage of solutes and immune cells from the bloodstream to the inflammatory focus in the tissue. Leukocytes first traverse endothelial barriers and then interact with parenchymal cell barriers. The latter often contain dysfunctional, damaged or highly inflamed cells that constitute the final destination of migrating leukocytes. In the liver parenchyma, leukocyte infiltration is essential to control cancer, infections and hepatic inflammatory diseases.

 

Endothelial cells line the inner surface of the vascular wall, where they form a selective barrier that controls the passage of cells and solutes between the blood and the parenchyma in the inflamed tissue. Our group is interested in investigating the effect of TNF on endothelial barrier disruption, using human primary endothelial cells as our main experimental model. First, we are studying the effect of this cytokine on the association of filamentous actin to cell-cell junctions. We are analyzing how TNF alters the localization and expression of receptors involved in leukocyte transendothelial migration, namely PECAM-1 and ICAM-1, which also regulate endothelial permeability. In addition, by combining proteomics, quantitative PCR and immunodetection we have identified a new set of proteins whose expression is regulated in response to TNF. We are currently analyzing the role of some of these proteins in TNF-induced endothelial barrier disruption, with the long-term aim of finding new targets to control the dysfunctional increase of vascular leakiness, which contributes to the development of  pro inflammatory diseases.

In addition, thanks to the support of the Instituto de Investigación Sanitaria Fundación Jiménez Díaz, we are currently investigating the effect of various inflammatory mediators on corneal endothelial barrier function, with the ultimate aim of preventing corneal opacity in eye inflammatory diseases.

Once leukocytes traverse the endothelial barrier in an organ, they establish adhesions with parenchymal cells, searching for the inflammatory focus and for dysfunctional cells. The liver is a paradigm of organ in which leukocyte infiltration into the parenchyma is essential for immune-surveillance, control of cancer and infections and tissue regeneration. We are currently studying the effect of TNF on human hepatic cell barriers and how these barriers control leukocyte trafficking in the parenchyma during inflammation.


Recent publications (2012-2016):

 

- Ortega MC, Santander-García D, Marcos-Ramiro, B, Barroso S, Cox S, Jiménez-Alfaro I and Millán J. Activation of Rac1 and RhoA preserve corneal endothelial barrier function. Investigative Ophthalmology & Visual Science November 2016, Vol.57, 6210-6222. doi:10.1167/iovs.16-20031

- Santander-García D, Ortega MC, Benito-Martínez S, Barroso S, Jiménez-Alfaro I and Millán J. A human cellular system for analyzing signaling during corneal endothelial barrier dysfunction. Experimental Eye Research. October 2016. http://dx.doi.org/10.1016/j.exer.2016.09.010

- García-Weber D and Millán, J. Parallels between single cell migration and barrier formation: the case of RhoB and Rac1 trafficking. Small GTPases; 2016, http://dx.doi.org/10.1080/21541248.2016.1231655.

- Marcos-Ramiro B, García-Weber D, Barroso S, Feito, J, Ortega MC, Cernuda-Morollón, E, Reglero-Real N, Fernández-Martín L, Alonso MA, Correas I, Ridley AJ and Millán J. RhoB controls endothelial barrier recovery by inhibiting Rac1 trafficking to the cell border. Journal of Cell Biology; 2016, 213(3):385-402.

- Reglero-Real R, García-Weber D and Millán J. Cellular Barriers after Extravasation: Leukocyte Interactions with Polarized Epithelia in the Inflamed Tissue. Mediators of Inflammation; 2016, http://dx.doi.org/10.1155/2016/7650260.

 

- Bernabé-Rubio M, Andrés G, Casares-Arias J, Fernández-Barrera J, Rangel L, Reglero-Real N, Gershlick DC, Fernández JJ, Millán J, Correas I, Miguez DG, Alonso MA. New role of the midbody in primary ciliogenesis by polarized epithelial cells. Journal of Cell Biology; 2016, 214(3):259-273.

 

- Rodríguez-Fraticelli AE, Bagwell J, Bosch-Fortea M, Boncompain G, Reglero-Real N, García-León MJ, Andrés G, Toribio ML, Alonso MA, Millán J, Perez F, Bagnat M, Martín-Belmonte F.Developmental regulation of apical endocytosis controls epithelial patterning in vertebrate tubular organs. Nature Cell Biology, 2015 Mar;17(3):241-50

 

- Marcos-Ramiro B, García-Weber D, Millán J. TNF-induced endothelial barrier disruption: beyond actin and Rho. Thrombosis and Haemostasis; 2014, 112(6):1088-10.

- Marcos-Ramiro B, Oliva-Nacarino, P., Serrano-Pertierra, E., Blanco-Gelaz, M.A., Weksler, B.B., Romero I.A., Couraud, P.O., Tuñon, A., Lopez-Larrea, C., Millán, J. (c.a), and Cernuda, E. (c.a) Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function. BMC Neuroscience; 2014, 12: 110. doi:10.1186/1471-2202-15-110.

- Reglero-Real R, Álvarez-Varela A, Cernuda-Morollón E, Feito J, Marcos-Ramiro B, Fernández-Martín L, Gómez-Lechón MJ, Muntané J, Sandoval P, Majano PL, Correas I, Alonso MA and Millán J. Apicobasal polarity controls lymphocyte adhesion to hepatic epithelial cells. Cell Reports; 2014 ;8(6):1879-93.

- Aranda J.F., Reglero-Real N., Marcos-Ramiro B. Ruiz-Sáenz A., Fernández-Martín L., Bernabé-Rubio M., Kremer L., Ridley A.J., Correas I., Alonso M.A. and Millán, J. MYADM controls endothelial barrier function through ERM-dependent regulation of ICAM-1 expression. Molecular Biology of the Cell; 2013, Feb;24(4):483-94.

- Ruiz-Saenz A, van Haren J, Sayas CL, Rangel L, Demmers J, Millán J, Alonso MA, Galjart N, Correas I. Protein 4.1R binds to CLASP2 and regulates dynamics, organization and attachment of microtubules to the cell cortex. Journal of Cell Science. 2013 Oct 15;126(Pt 20):4589-601

- Fernández-Martín, L. Marcos-Ramiro, B., Bigarella, CL. Graupera,  M. Cain, RJ.  Reglero-Real, N., Jiménez A, Cernuda-Morollón, E., Correas, I. Cox, S., Ridley, AJ and Millán J. Crosstalk between Reticular Adherens Junctions and PECAM-1 Regulates Endothelial Barrier Function. Arteriosclerosis Thrombosis Vascular Biology. 2012. 32(8):e90-e102.         

- Reglero-Real, N., Marcos-Ramiro, B. and Millán J. Endothelial membrane reorganization during leukocyte extravasation. Cell Molecular Life Sciences. 2012. Sep;69(18):3079-99.


 

Doctoral Theses:

- Natalia Reglero Real (2013). Función de la polaridad apicobasal de las células hepáticas en la adhesion linfocitaria. Implicaciones en la respuesta inflamatoria del hígado.

- Beatriz Marcos Ramiro (2015). La GTPasa endosomal RhoB regula la recuperación de la barrera endotelial durante la inflamación.


More Information in external link:

http://jmillan4.wix.com/cellbiolinflammation

Cell Biology and Immunology
  Mitochondrial pathophysiology

 

 
grupo-cadenas400px

 


 

 

Susana Cadenas

 ASciStaff

APublications

 

 

 

 

Research summary:

     Fig1-300

 

Hydrogen peroxide (H2O2) or conditions leading to H2O2 formation such as ischemia-reperfusion injury, increases UCP3 expression via Nrf2, promoting cell survival under conditions of oxidative stress.

Research in our group is focused on the function of mitochondria within cells and their implication in the development of pathological conditions. Mitochondria are a major source of reactive oxygen species (ROS) in cells. Uncoupling proteins 2 and 3 (UCP2, UCP3) might be involved in controlling the production of mitochondrial ROS and protecting against oxidative stress, although the mechanism is unclear. UCPs are activated by superoxide and the lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE), to induce proton leak leading to membrane depolarization (mild uncoupling) and the decrease in ROS production. In addition, UCP2 and UCP3 are controlled by covalent modification by glutathione. We have recently found that the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of the cellular antioxidant response, induces UCP3 expression under conditions of oxidative stress (Anedda et al., Free Radic. Biol. Med. 2013). We are currently investigating the effects of 4-HNE on UCP3 expression and function in cardiomyocytes and their functional consequences.

Ischemia-reperfusion (IR) injury in myocardial infarction is caused, in part, by oxidative damage. It has been shown that 4-HNE-induced Nrf2 activation protects against cardiac IR. We aim to determine the potential cardioprotective role of UCP3 against IR damage and its role during ischemic preconditioning (IPC), a protective mechanism that consists of brief ischemic episodes prior to prolonged ischemia, in the intact perfused mouse heart. Other redox-sensitive signaling pathways involved in IPC, such as PTEN oxidation and PI3K/Akt activation, are also the focus of our investigation.


 

Relevant publications:

  • Anedda A, López-Bernardo E, Acosta-Iborra B, Suleiman MS, Landázuri MO, Cadenas S. The transcription factor Nrf2 promotes survival by enhancing the expression of uncoupling protein 3 under conditions of oxidative stress. Free Radic. Biol. Med. 61C, 395-407 (2013)
  • Aguirre E, López-Bernardo E, Cadenas S. Functional evidence for nitric oxide production by skeletal muscle mitochondria from lipopolysaccharide-treated mice. Mitochondrion 12, 126-131 (2012)
  • Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordoñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO. Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting Complex I activity. Cell Metab 14, 768-779 (2011)
  • Cadenas S, Aragonés J, Landázuri MO. Mitochondrial reprogramming through cardiac oxygen sensors in ischemic heart disease. Cardiovasc. Res. 88, 219-228 (2010)
  • Aguirre E, Cadenas S. GDP and carboxyatractylate inhibit 4-hydroxynonenal-activated proton conductance to differing degrees in mitochondria from skeletal muscle and heart. Biochim. Biophys. Acta 1797, 1716-1726 (2010)
  • Aguirre E, Rodríguez-Juárez F, Bellelli A, Gnaiger E, Cadenas S. Kinetic model of the inhibition of respiration by endogenous nitric oxide in intact cells. Biochim. Biophys. Acta 1797, 557-565 (2010)

 

Doctoral Theses:

Elia López-Bernardo (en curso) Regulación de la expresión y función de la proteína desacoplante UCP3 por el estrés oxidativo: implicaciones en isquemia-reperfusión cardiaca. Universidad Autónoma de Madrid. Directora: Susana Cadenas

Félix Rodríguez-Juárez (2009) Efectos del óxido nítrico endógeno sobre la guanilato ciclasa soluble, la respiración y la conductancia de la membrana mitocondrial interna a los protones en células intactas. Universidad Autónoma de Madrid. Directora: Susana Cadenas

Enara Aguirre (2009) Estudio del papel protector de la proteína desacoplante UCP3 frente al estrés oxidativo en mitocondrias de músculo esquelético y corazón de ratones tratados con endotoxina y en cardiomiocitos de rata. Universidad Complutense de Madrid. Directora: Susana Cadenas

Mitochondrial pathophysiology


Grupo-400

 


 

 

Susana Cadenas

 ASciStaff

APublications

 

 

 

 

Research summary:

     Figure1-300

 

Hydrogen peroxide (H2O2) and 4-hydroxynonenal (HNE), or conditions leading to an increase in these compounds such as ischemia-reperfusion, increase UCP3 expression via Nrf2, promoting cell survival under conditions of oxidative stress.

 

 

 

 

 

Research in our group is focused on the function of mitochondria within cells and their implication in the development of pathological conditions. Mitochondria are a major source of reactive oxygen species (ROS) in cells. Uncoupling proteins 2 and 3 (UCP2, UCP3) might be involved in controlling the production of mitochondrial ROS and protecting against oxidative stress, although the mechanism is unclear. UCPs are activated by superoxide and the lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE), to induce proton leak leading to membrane depolarization (mild uncoupling) and the decrease in ROS production. In addition, UCP2 and UCP3 are controlled by covalent modification by glutathione. We have recently found that the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of the cellular antioxidant response, induces UCP3 expression under conditions of oxidative stress (Anedda et al., Free Radic. Biol. Med. 2013). We are currently investigating the effects of 4-HNE on UCP3 expression and function in cardiomyocytes and their functional consequences.

Ischemia-reperfusion (IR) injury in myocardial infarction is caused, in part, by oxidative damage. It has been shown that 4-HNE-induced Nrf2 activation protects against cardiac IR. We aim to determine the potential cardioprotective role of UCP3 against IR damage and its role during ischemic preconditioning (IPC), a protective mechanism that consists of brief ischemic episodes prior to prolonged ischemia, in the intact perfused mouse heart. Other redox-sensitive signaling pathways involved in IPC, such as PTEN oxidation and PI3K/Akt activation, are also the focus of our investigation.


 

Relevant publications:

  • López-Bernardo E, Anedda A, Sánchez-Pérez P, Acosta-Iborra B, Cadenas S. 4-Hydroxynonenal induces Nrf2-mediated UCP3 upregulation in mouse cardiomyocytes. Free Radic. Biol. Med. (2015) doi: 10.1016/j.freeradbiomed.2015.03.032
  • Anedda A, López-Bernardo E, Acosta-Iborra B, Suleiman MS, Landázuri MO, Cadenas S. The transcription factor Nrf2 promotes survival by enhancing the expression of uncoupling protein 3 under conditions of oxidative stress. Free Radic. Biol. Med. 61C, 395-407 (2013)
  • Aguirre E, López-Bernardo E, Cadenas S. Functional evidence for nitric oxide production by skeletal muscle mitochondria from lipopolysaccharide-treated mice. Mitochondrion 12, 126-131 (2012)
  • Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordoñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO. Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting Complex I activity. Cell Metab 14, 768-779 (2011)
  • Cadenas S, Aragonés J, Landázuri MO. Mitochondrial reprogramming through cardiac oxygen sensors in ischemic heart disease. Cardiovasc. Res. 88, 219-228 (2010)
  • Aguirre E, Cadenas S. GDP and carboxyatractylate inhibit 4-hydroxynonenal-activated proton conductance to differing degrees in mitochondria from skeletal muscle and heart. Biochim. Biophys. Acta 1797, 1716-1726 (2010)
  • Aguirre E, Rodríguez-Juárez F, Bellelli A, Gnaiger E, Cadenas S. Kinetic model of the inhibition of respiration by endogenous nitric oxide in intact cells. Biochim. Biophys. Acta 1797, 557-565 (2010)

 

Doctoral Theses:

Elia López-Bernardo (2015) Regulation of the expression and function of mitochondrial uncoupling protein UCP3 in response to oxidative stress: involvement of the transcription factor Nrf2 and implications in cardiac ischemia-reperfusion. Universidad Autónoma de Madrid. Directora: Susana Cadenas

Félix Rodríguez-Juárez (2009) Efectos del óxido nítrico endógeno sobre la guanilato ciclasa soluble, la respiración y la conductancia de la membrana mitocondrial interna a los protones en células intactas. Universidad Autónoma de Madrid. Directora: Susana Cadenas

Enara Aguirre (2009) Estudio del papel protector de la proteína desacoplante UCP3 frente al estrés oxidativo en mitocondrias de músculo esquelético y corazón de ratones tratados con endotoxina y en cardiomiocitos de rata. Universidad Complutense de Madrid. Directora: Susana Cadenas

 

Cell Biology and Immunology
               Bioinformatics Unit

 

 

Grupo400
 


 

 

Ugo Bastolla

 ASciStaff

APublications

 

 

 

 

Research summary:

  -----  Fig01-300
 

 

Disordered regions are abundant in protein complexes such as the Centrosome. Their evolution through large insertions is accelerated along branches in which the complexity of the organism increased more.

 

 

Fig02-300 
  Composite view depicting our interests and accomplishments in docking and scoring.
   
   

1) Stability, dynamics and evolution of proteins. Our group develops mathematical models for predicting protein folding stability, the effect of mutations, stability against misfolding and the corresponding selective pressures. We apply these models to simulate protein evolution and the effect of the evolutionary process (mutation rate, mutation bias, population size) on protein stability. Our torsional network model (TNM) allows simulating the equilibrium dynamics of proteins, characterizing allosteric and catalytic sites, and telling functional movements from conformation changes in response to a random perturbation. Within the TNM, we are developing an energy function to predict conformation changes and energy barriers. We study the evolution of disordered protein regions and their contribution to organism complexity.

2) Theoretical ecology and bacterial networks. We investigate the factors that influence ecosystem diversity, in particular competition and mutualism. By analyzing co-occurrences of bacteria in environmental samples, we predict their interaction networks and we proposed that mutualistic interactions favor bacterial cosmopolitanism and biodiversity.

3) Next generation sequencing. We developed the algorithm ZPeaks to detect peaks in sequencing experiments, and we applied it to the analysis of replication origins.

4) Drug design (line directed by Antonio Morreale). We completed a new version of our automatic platform for virtual screening VSDMIP, which allows finding candidate drugs based on the structure of the target protein or of known ligands, exploiting the graphical interface of the program PyMOL. We improved our docking algorithm and our scoring function, and we explored a new approach to drug design. Our new web application AtlasCBS allows mapping the chemical-biological space of drug design. Our experience with molecular modeling produced several collaborations, within as well as outside the CBMSO, and a patent application.


 

Relevant publications:

  • Bastolla, U., Bruscolini, P., and Velasco, J.L. (2012) Sequence determinants of protein folding rates: Positive correlation between contact energy and contact range indicates selection for fast folding. Proteins 80:2287-2304.
  • Liberles, D.A., et al. (2012) The interface of protein structure, protein biophysics and molecular evolution. Protein Sci. 21:769-785.
  • Nido, G.S., Méndez, R., Pascual-García, A., Abia, D. and Bastolla, U. (2012) Protein disorder in the centrosome correlates with complexity in cell types number. Mol. BioSystems, 8:353-367.
  • Bastolla, U. and Porto, M. (2012) Modeling structural and genomic constraints in the evolution of proteins. In: Dokholyan, N. (ed) Computational Modeling of Biological Systems: From Molecules to Pathways. Springer Verlag, New York, U.S.A.
  • Maalej, E., Chabchoub, F., Samadi, A., de los Ríos, C., Perona, A., Morreale, A., and Marco-Contelles, J. (2011) Synthesis, biological assessment and molecular modeling of 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines. Bioorg. Med. Chem. Lett. 21, 2384-2388.

 

Other activities:

- Organización del congreso “The emerging dynamics view of proteins: Protein plasticity in allostery, evolution and self-assembly”, Dresden, Germany, julio 2012, organizadores: U. Bastolla, M. Porto and H.E. Roman.

- Editor del número especial de la revista Biophysica and Biochimica Acta (Elsevier) dedicada al congreso “The emerging dynamics view of proteins” (U. Bastolla)

- Editor de la revista Peer J. (U. Bastolla)

- Comité científico de las Jornadas de Bioinformática 2012 (U. Bastolla, A. Morreale)

- Coordinador del curso de bioinformática del Master de Biofísica UAM (A. Pascual-García). Clases de bioinformática en el master de biofísica UAM (D. Abia, U. Bastolla, A. Cortés, J. Klett, R. Méndez, A. Morreale, A. Pascual-García), seminario en el master de bioinformática UCM (U. Bastolla)

- Curso 2011-2012 de Sistemas Biológicos en el grado de Ingeniería Biomédica de la Universidad Carlos III de Madrid (U. Bastolla).

- Solicitud de patente: F. Mayor-Menéndez, C. Murga-Montesinos, P.M. Campos-Muelas, J.J. Heijnen, A.M. Agnes, A. Kavelaars, A. Morreale y R. Gil. Nuevos compuestos inhibidores de p38MAPK y sus aplicaciones. N. de solicitud P201131754, 2 de noviembre de 2011. Propietario: UAM.

- Organización del taller práctico “Docking y cribado virtual: uso de herramientas computacionales en el diseño de fármacos”. 20-22 de junio de 2011, Madrid (A. Morreale)

- Presentaciones orales en congresos:

- U. Bastolla, Characterization of conformation changes in proteins with the torsional network model. Workshop “Allosteric Regulation of Cell Signalling”, CNIO, Madrid,17-19 September 2012.

- U. Bastolla, Modeling the mutual influence between folding and evolution. Workshop: Modeling protein structural and energetic constraints on sequence evolution. Durham, USA, Nov. 2011

- U. Bastolla, Contact interactions in proteins: Simple models give analytic insights on protein stability, evolution, and dynamics. Barcelona Supercomputing Center, Dec. 2011

- A. Pascual-García, Detecting bacterial interactions from environmental samples: Ecological aggregations favor bacterial cosmopolitanism. Jornadas de Bioinformática 2012, Barcelona.

- A. Morreale, A reverse combination of structure-based and ligand-based strategies for virtual screening. Jornadas de Bioinformática 2012, Barcelona.

http://ub.cbm.uam.es/home/overview.php?lang=es

Genetics susceptibility in complex diseases: genes involved in susceptibility to T-cell lymphoblastic lymphoma


Grupo-400

 


José Fernández Piqueras

ASciStaff

APublications

 

Research summary:

In the last five years we have been working on murine T-cell lymphoblastic lymphomas (T-LBLs) arising spontaneously in knockout mice and, in particular, with T-LBLs induced by gamma-irradiation in susceptible and resistant inbred strains, as well as in consomics and congenic derived strains.Results obtained in mouse are confirmed in human cell lines derived from this type of lymphomas and in primary T-LBLs.

 Fig01-300

Abnormal spectral karyotype of a murine T-LBL

Genome wide analyses using cDNA-expression arrays, CGH-arrays and epigenetic approaches, allowed us to identify multiple coding and non-coding (miRNAs) loci underlying genetic susceptibility in these lymphomas. Interestingly, some of these gene alterations occur exclusively in the stroma that accompanies lymphoma cells (ANXA1 and CD274). Other major achievements include the demonstration that down-regulation of specific miRNAs may explain the over-expression of critical oncogenes (as c-MYC, ABL1, BCR-ABL and SMO), and that several tumour suppressor genes (in particular CDKN2A, CDKN2B, and EPHA7) are silenced by the combinatory effect of deletion on one allele and the epigenetic inactivation of the other one

Fig02-300

 

   

   fig03-300

 

    

 fig04-300

Transcriptional miRNA profiling of murine T-LBLs

------ Genome-wide analysis of copy-number variations (aCGH) and critical coding and non-coding genes involved in  murine T-LBL development ------ Methylation analysis of CpG-islands at the promoter region of EPHA7 gene in human T-LBL samples. MSP and Bisulphite-sequencing.

Over this time, we have registered three patents. Present and future initiatives of our group are (1) to assess the oncogenic potential of over-expression of critical oncogenes exhibiting very low rates of mutations using adoptive transfer approaches with different types of genetically-modified hematopoietic-stem cells, (2) to identify the genetic and epigenetic changes associated with the different stages of T-LBL development (3) to unravel how the deregulation of Fas apoptotic signalling is contributing to T-LBL development (4) to exploit the collateral damage of common deletions to kill lymphoma cells,  and (5) to integrate the results of all genomic approaches into a map of genetic and epigenetic alterations for human T-LBLs  in order to improve prognosis and diagnosis, and to design more effective therapies.


Relevant publications:

  • Bueno MJ, Gómez de Cedrón M, Pérez de Castro I, Gómez-López G, Di Lisio L, Montes Moreno S, Martínez N, Guerrero M, Sánchez-Martínez R, Santos J, Pisano, DG, Piris MA, Fernández-Piqueras J and Malumbres M (2011) Combinatorial effects of microRNAs to suppress the Myc oncogenic pathway. Blood 117(23): 6255-66.
  • Bueno MJ, Gómez de Cedrón M, Laresgoiti U, Fernández-Piqueras J, Zubiaga A and Malumbres M (2010) Multiple E2F-induced microRNAs prevent replicative stress in response to mitogenic signalling. Molecular Cellular Biology 30 (12): 2983-2995.
  • Santos J, González-Sánchez L, Matabuena-de Yzaguirre M, Villa-Morales M, Cozar P, López-Nieva P, Fernández-Navarro P, Fresno M, Díaz MD, Guenet JL, Montagutelli X & Fernández-Piqueras J. (2009) A role for stroma-derived Annexin A1 as mediator in the control of genetic susceptibility to T-cell lymphoblastic malignancies through PGE2 secretion. Cancer Res 69(6): 2577-87.
  • Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC, Croce CM, Fernandez-Piqueras J, Malumbres M (2008) Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell, 13: 496-506.
  • Villa-Morales M, Santos J, Pérez-Gómez E, Quintanilla M and Fernández-Piqueras J (2007) A role for the Fas/FasL system in modulating genetic susceptibility to T-cell lymphoblastic lymphomas. Cancer Res 67 (11): 5107-5116.

Immunoregulatory mechanisms in the development of Chagas disease: translational applications

 

 


Núria Gironès Pujol

ASciStaff

APublications

Chagas disease caused byTrypanosoma cruzi affects approximately 10 million people in Latin America.  Besides, blood transfusion and organ transplantation is a sanitary problem in countries receptors of migrants from endemic areas. Cardiac pathology is the most severe and characteristic manifestation and it is estimated a future incidence between 6.000 y 30.000 cases of chagasic cardiomyopathy in Spain.

Our working hypothesis is that development of pathology depends on a combination of factors: host genetic background, different parasite infecting capacities with different genetic backgrounds and the regulatory immune response will affect the inflammatory process. In this context, our goal is the study of the regulatory response, through myeloid-derived suppressor cells and regulatory T cells during experimental infection in the mouse model, further studying and identifying regulatory cell populations in the inflammatory infiltrate implicated in controlling parasite replication and/or tissue damage. 

Our interest for translational application of our research let us to maintain scientific collaborations with Spanish and foreign groups, basic and clinical, for the evaluation of new prognostic and follow up biomarkers, needed for deciding treatment of patients and its efficacy. For this, we use “Omics” tools as Genomics, Transcriptomics, Proteomics and Metabolomics.

 

Relevant publications

Genomic assemblies of newly sequenced Trypanosoma cruzi strains reveal new genomic expansion and greater complexity. Callejas-Hernández F, C., Rastrojo A, Poveda C, Gironès N1c and Fresno M1c. Scientific Reports, 2018. 8:14631. doi:10.1038/s41598-018-32877-2. IF: 4,259; Q1.

Regulatory Lymphoid and Myeloid Cells Determine the Cardiac Immunopathogenesis of Trypanosoma cruzi Infection. Fresno M, Gironès Nc. Front Microbiol. 2018 Mar 1;9:351. doi: 10.3389/fmicb.2018.00351. IF: 4.076; Q1.

L-arginine supplementation reduces mortality and improves disease outcome in mice infected with Trypanosoma cruzi. Carbajosa S, Rodríguez-Angulo HO, Gea S, Chillón-Marinas C, Poveda C, Maza MC, Colombet D, Fresno M1, Gironès N1c. PLoS Negl Trop Dis. 2018 Jan 16;12(1):e0006179. doi: 10.1371/journal.pntd.0006179 IF: 3.834; Q1.

Altered bone marrow lymphopoiesis and interleukin-6-dependent inhibition of thymocyte differentiation contribute to thymic atrophy during Trypanosoma cruzi infection. Carbajosa S, Gea S, Chillón-Marinas C, Poveda C, Del Carmen Maza M, Fresno M1, Gironès N1c. Oncotarget. 2017 Mar 14;8(11):17551-17561. doi: 10.18632/oncotarget.14886. IF: 5.168; Q1.

Cyclooxygenase-2 and Prostaglandin E2 Signaling through Prostaglandin Receptor EP-2 Favor the Development of Myocarditis during Acute Trypanosoma cruzi Infection. Guerrero NA, Camacho M, Vila L, Íñiguez MA, Chillón-Marinas C, Cuervo H, Poveda C, Fresno M1, Gironès N1c. PLoS Negl Trop Dis. 2015 Aug 25;9(8):e0004025. doi: 10.1371/journal.pntd.0004025. IF: 3.834; Q1.

Global metabolomic profiling of acute myocarditis caused by Trypanosoma cruzi infection. Gironès Nc, Carbajosa S, Guerrero NA, Poveda C, Chillón-Marinas C, Fresno M. PLoS Negl Trop Dis. 2014 Nov 20;8(11):e3337. doi: 10.1371/journal.pntd.0003337 IF: 3.834; Q1.

Analysis of the Dynamics of Infiltrating CD4(+) T Cell Subsets in the Heart during Experimental Trypanosoma cruzi Infection. Sanoja C, Carbajosa S, Fresno M1, Gironès N1c. PLoS One. 2013 Jun 11;8(6):e65820 . IF: 2.766; Q1.

Myeloid-derived suppressor cells infiltrate the heart in acute Trypanosoma cruzi infection. Cuervo H, Guerrero NA, Carbajosa S, Beschin A, De Baetselier P, Gironès N1c, Fresno M1. J Immunol. 2011 Sep 1;187(5):2656-65. IF: 5.788; Q1.

Nitric Oxide Synthase and Arginase Expression in Heart Tissue during Acute Trypanosoma cruzi Infection in Mice: Arginase I Is Expressed in Infiltrating CD68(+) Macrophages. Cuervo H., Pineda M. A., Aoki M. P., Gea S., Fresno M1. and Gironès N1c. Inducible Nitric J Infect Dis. 2008 May 12. . IF: 5.682; Q1.

c corresponding author. 1 equal contribution to the direction of the work.

 

Metabolic homeostasis

 

Grup ISandoval 400
 


Ignacio Vicente Sandoval

ASciStaff

APublications

 

Research summary:

 .....

..Fig01 300px

 jjjj

Cu+- induced relocation of the Cu+ transporter ATP7B from the trans-Golgi network to the bile canaliculus in CAN 10 hepatoma cells. Cells treated with Cu+ as indicated in the panels were studied for ATP7B location. Note the early transit of ATP7B through the cell basolateral domain (area delineated by the white dotted lines and the far end of the β catenin labelled plasma membrane) and the localization of ATP7B in the bile canaliculi, sealed by the ZO-1 positive tight junctions, after extensive treatment with Cu+.

 

 

 

 

 

 

 

 

 

 

 

The transition metal copper (Cu+) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and potentially damaging to the cell. Free Cu is virtually absent in the cell. In mammalians liver is the major captor, distributor and excreter of Cu. Humans eliminate 95% of the Cu+ ingested with diet. The excretion of Cu into the bile is an attribute exclusive of the hepatocyte and bile is the major route of Cu elimination and the most important mechanism in Cu homoeostasis in mammals. The correlation between the release of ATP7B retained in the trans-Golgi network (TGN) and the role of ATP7B in excretion of Cu into the bile is firmly established. Yet, the pathway of ATP7B transport is poorly understood and its site of action is the subject of a hot debate. Our studies of Cu+-mediated ATP7B traffic in CAN 10 hepatoma cells showed that after its release from the TGN, ATP7B is basolateral sorted, inserted in the basolateral plasma membrane and transported by transcytosis to the bile canaliculus (BC). Insertion of ATP7B into the membrane of the BC is essential for excreting excess of cellular Cu+ into the medium. Contradicting recent reports, our studies find no evidence of ATP7B association with lysosomes and do not support the recent model of Cu+ excretion mediated by lysosome exocytosis. In recent months we have started a systematic study of the mutations that disrupt ATP7B traffic and cause Wilson disease and cuprotoxicosis with a genetic background of wild ATP7B. In a separate study we investigate the role of ESyt proteins in membrane dynamics and glucose and lipid metabolism in the adipocyte. New inroads in understanding the functioning of Esyt3, a protein associated with the endoplasmic reticulum (ER) that is believed to play a key role in anchoring the ER to the plasma membrane, include: the mapping of the Ca++ and phospholipid binding to the BM y C2-1,C2-2 y C2-3 domains; the characterization of its physical interaction with gelsolin; its role in lipid droplet biogenesis. Finally the study of the toroidal structure produced by polymerization of IMPDH2 is in progress and the study of the HDAC enhancer C6orf89 has been completed.


 

Relevant publications:

  • DKWSLLL, a versatile DXXXLL-type signal with distinct roles in the Cu(+)-regulated trafficking of ATP7B.Lalioti V, Hernandez-Tiedra S, Sandoval IV.Traffic. 2014 Aug;15(8):839-60. 2014 Jun 24.
  • Sorcin links calcium signaling to vesicle trafficking, regulates Polo-like kinase 1 and is necessary for mitosis. Lalioti VS, Ilari A, O'Connell DJ, Poser E, Sandoval IV, Colotti G.PLoS One. 2014 Jan 10;
  • Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS. Colanzi A, Grimaldi G, Catara G, Valente C, Cericola C, Liberali P, Ronci M, Lalioti VS, Bruno A, Beccari AR, Urbani A, De Flora A, Nardini M, Bolognesi M, Luini A, Corda D. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9794-9. doi: 10.1073/pnas.1222413110. Epub 2013 May 28.
  • C6orf89 encodes three distinct HDAC enhancers that function in the nucleolus, the golgi and the midbody. Lalioti VS, Vergarajauregui S, Villasante A, Pulido D, Sandoval IV.J Cell Physiol. 2013 Sep;228(9):1907-21.

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