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Bonzon-Kulichenko, Elena

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Elena
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Bonzon-Kulichenko
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CNIC
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2015 - 201992020 - 202312
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    USP49 deubiquitinase regulates the mitotic spindle checkpoint and prevents aneuploidy.
    (Springer, 2023-01-26) Campos-Iglesias, Diana; Fraile, Julia M; Bretones, Gabriel; Montero, Alejandro A; Bonzon-Kulichenko, Elena; Vazquez, Jesus; López-Otín, Carlos; Freije, José M P; Ministerio de Ciencia e Innovación (España); Fundación La Caixa; Unión Europea. Comisión Europea. European Research Council (ERC); Fundación Cajastur-Liberbank
    The spindle assembly checkpoint (SAC) is an essential mechanism that ensures the accurate chromosome segregation during mitosis, thus preventing genomic instability. Deubiquitinases have emerged as key regulators of the SAC, mainly by determining the fate of proteins during cell cycle progression. Here, we identify USP49 deubiquitinase as a novel regulator of the spindle checkpoint. We show that loss of USP49 in different cancer cell lines impairs proliferation and increases aneuploidy. In addition, USP49-depleted cells overcome the arrest induced by the SAC in the presence of nocodazole. Finally, we report new binding partners of USP49, including ribophorin 1, USP44, and different centrins.
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    Activation of Serine One-Carbon Metabolism by Calcineurin A beta 1 Reduces Myocardial Hypertrophy and Improves Ventricular Function
    (Elsevier, 2018) Padron-Barthe, Laura; Villalba-Orero, Maria; Gomez-Salinero, Jesus M.; Acin-Perez, Rebeca; Cogliati, Sara; Lopez-Olaneta, Marina; Ortiz-Sanchez, Paula; Bonzon-Kulichenko, Elena; Vazquez, Jesus; Garcia-Pavia, Pablo; Rosenthal, Nadia; Enriquez, Jose Antonio; Lara-Pezzi, Enrique; Unión Europea. Comisión Europea; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III; Comunidad de Madrid (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Fundación ProCNIC
    BACKGROUND In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria. OBJECTIVES The authors aimed to determine the role of the calcineurin splicing variant CnA beta 1 in the context of cardiac hypertrophy and its mechanism of action. METHODS Transgenic mice overexpressing CnAb1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnA beta 1 (CnA beta 1(Delta i12) mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses. RESULTS In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnA beta 1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAb1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnA beta 1. CnA beta 1(Delta i12) mice show increased cardiac hypertrophy and declined contractility. CONCLUSIONS The metabolic reprogramming induced by CnAb1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches. (J Am Coll Cardiol 2018; 71: 654-67) (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
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    Defective dimerization of FoF1-ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging.
    (Wiley, 2022-03) Bou-Teen, Diana; Fernandez-Sanz, Celia; Miro-Casas, Elisabet; Nichtova, Zuzana; Bonzon-Kulichenko, Elena; Casós, Kelly; Inserte, Javier; Rodriguez-Sinovas, Antonio; Benito, Begoña; Sheu, Shey-Shing; Vazquez, Jesus; Ferreira-González, Ignacio; Ruiz-Meana, Marisol; Instituto de Salud Carlos III; Ministerio de Salud (España); Sociedad Española de Cardiología
    Aged cardiomyocytes develop a mismatch between energy demand and supply, the severity of which determines the onset of heart failure, and become prone to undergo cell death. The FoF1-ATP synthase is the molecular machine that provides >90% of the ATP consumed by healthy cardiomyocytes and is proposed to form the mitochondrial permeability transition pore (mPTP), an energy-dissipating channel involved in cell death. We investigated whether aging alters FoF1-ATP synthase self-assembly, a fundamental biological process involved in mitochondrial cristae morphology and energy efficiency, and the functional consequences this may have. Purified heart mitochondria and cardiomyocytes from aging mice displayed an impaired dimerization of FoF1-ATP synthase (blue native and proximity ligation assay), associated with abnormal mitochondrial cristae tip curvature (TEM). Defective dimerization did not modify the in vitro hydrolase activity of FoF1-ATP synthase but reduced the efficiency of oxidative phosphorylation in intact mitochondria (in which membrane architecture plays a fundamental role) and increased cardiomyocytes' susceptibility to undergo energy collapse by mPTP. High throughput proteomics and fluorescence immunolabeling identified glycation of 5 subunits of FoF1-ATP synthase as the causative mechanism of the altered dimerization. In vitro induction of FoF1-ATP synthase glycation in H9c2 myoblasts recapitulated the age-related defective FoF1-ATP synthase assembly, reduced the relative contribution of oxidative phosphorylation to cell energy metabolism, and increased mPTP susceptibility. These results identify altered dimerization of FoF1-ATP synthase secondary to enzyme glycation as a novel pathophysiological mechanism involved in mitochondrial cristae remodeling, energy deficiency, and increased vulnerability of cardiomyocytes to undergo mitochondrial failure during aging.
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    Basal oxidation of conserved cysteines modulates cardiac titin stiffness and dynamics
    (Elsevier, 2022-03-28) Herrero-Galan, Elas; Martinez-Martin, Ines; Sanchez-Gonzalez, Cristina; Vicente, Natalia; Bonzon-Kulichenko, Elena; Calvo, Enrique; Suay-Corredera, Carmen; Pricolo, Maria Rosaria; Fernández-Trasancos, Ángel; Velázquez-Carreras, Diana; Badia-Careaga, Claudio; Abdellatif, Mahmoud; Sedej, Simon; Rainer, Peter P.; Giganti, David; Pérez-Jiménez, Raúl; Vazquez, Jesus; Alegre-Cebollada, Jorge; Ministerio de Ciencia e Innovación (España); Comunidad de Madrid (España); Instituto de Salud Carlos III; Fundación La Caixa; FWF Austrian Science Fund; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
    Titin, as the main protein responsible for the passive stiffness of the sarcomere, plays a key role in diastolic function and is a determinant factor in the etiology of heart disease. Titin stiffness depends on unfolding and folding transitions of immunoglobulin-like (Ig) domains of the I-band, and recent studies have shown that oxidative modifications of cryptic cysteines belonging to these Ig domains modulate their mechanical properties in vitro. However, the relevance of this mode of titin mechanical modulation in vivo remains largely unknown. Here, we describe the high evolutionary conservation of titin mechanical cysteines and show that they are remarkably oxidized in murine cardiac tissue. Mass spectrometry analyses indicate a similar landscape of basal oxidation in murine and human myocardium. Monte Carlo simulations illustrate how disulfides and S-thiolations on these cysteines increase the dynamics of the protein at physiological forces, while enabling load- and isoform-dependent regulation of titin stiffness. Our results demonstrate the role of conserved cysteines in the modulation of titin mechanical properties in vivo and point to potential redox-based pathomechanisms in heart disease.
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    Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
    (American Heart Association (AHA), 2022-04-05) Lechuga-Vieco, Ana Victoria; Latorre-Pellicer, Ana; Calvo, Enrique; Torroja, Carlos; Pellico, Juan; Acin-Perez, Rebeca; García-Gil, María Luisa; Santos, Arnoldo; Bagwan, Navratan; Bonzon-Kulichenko, Elena; Magni, Ricardo; Benito, Marina; Justo-Méndez, Raquel; Simon, Anna Katharina; Sanchez-Cabo, Fatima; Vazquez, Jesus; Ruíz-Cabello, Jesús; Enriquez, Jose Antonio; Ministerio de Ciencia e Innovación (España); European Molecular Biology Organization; Humand Frontier Science Program; Ministerio de Economía, Industria y Competitividad (España); Programa Red Guipuzcoana de Ciencia, Tecnología e Información; Basque Government (España); ELKARTEK Program; Fundación BBVA; Ministerio de Ciencia e Innovación. Unidades de Excelencia María de Maeztu. (España); Unión Europea. Comisión Europea. H2020; Marie Curie; Fundación La Marató TV3; Fundación La Caixa; Instituto de Salud Carlos III; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Agencia Estatal de Investigación (España)
    In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism. We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.
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    Unbiased plasma proteomics discovery of biomarkers for improved detection of subclinical atherosclerosis.
    (Elsevier, 2022-02) Nunez, Estefania; Fuster, Valentin; Gómez-Serrano, María; Valdivielso, José Manuel; Fernández-Alvira, Juan Miguel; Martínez-López, Diego; Rodriguez, Jose Manuel; Bonzon-Kulichenko, Elena; Calvo, Enrique; Alfayate, Alvaro; Bermudez-Lopez, Marcelino; Escola-Gil, Joan Carles; Fernández-Friera, Leticia; Cerro-Pardo, Isabel; Mendiguren, José María; Sanchez-Cabo, Fatima; Sanz, Javier; Ordovás, José María; Blanco-Colio, Luis Miguel; García-Ruiz, José Manuel; Ibáñez, Borja; Lara-Pezzi, Enrique; Fernández-Ortiz, Antonio; Martín-Ventura, José Luis; Vazquez, Jesus; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares); Centro de Investigación Biomédica en Red - CIBERDEM (Diabetes y Enfermedades Metabólicas asociadas); Fundación La Marató TV3; Fundación La Caixa; Banco Santander; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Fundación ProCNIC
    Imaging of subclinical atherosclerosis improves cardiovascular risk prediction on top of traditional risk factors. However, cardiovascular imaging is not universally available. This work aims to identify circulating proteins that could predict subclinical atherosclerosis. Hypothesis-free proteomics was used to analyze plasma from 444 subjects from PESA cohort study (222 with extensive atherosclerosis on imaging, and 222 matched controls) at two timepoints (three years apart) for discovery, and from 350 subjects from AWHS cohort study (175 subjects with extensive atherosclerosis on imaging and 175 matched controls) for external validation. A selected three-protein panel was further validated by immunoturbidimetry in the AWHS population and in 2999 subjects from ILERVAS cohort study. PIGR, IGHA2, APOA, HPT and HEP2 were associated with subclinical atherosclerosis independently from traditional risk factors at both timepoints in the discovery and validation cohorts. Multivariate analysis rendered a potential three-protein biomarker panel, including IGHA2, APOA and HPT. Immunoturbidimetry confirmed the independent associations of these three proteins with subclinical atherosclerosis in AWHS and ILERVAS. A machine-learning model with these three proteins was able to predict subclinical atherosclerosis in ILERVAS (AUC [95%CI]:0.73 [0.70-0.74], p < 1 × 10-99), and also in the subpopulation of individuals with low cardiovascular risk according to FHS 10-year score (0.71 [0.69-0.73], p < 1 × 10-69). Plasma levels of IGHA2, APOA and HPT are associated with subclinical atherosclerosis independently of traditional risk factors and offers potential to predict this disease. The panel could improve primary prevention strategies in areas where imaging is not available. This study was supported by competitive grants from the Spanish Ministry of Science, Innovation and Universities (BIO2015-67580-P, PGC2018-097019-B-I00, PID2019-106814RB-I00 and SAF2016-80843-R), through the Carlos III Institute of Health-Fondo de Investigacion Sanitaria grant PRB3 (IPT17/0019 - ISCIII-SGEFI / ERDF, ProteoRed), CIBERCV and CIBERDEM, the Fundacio MaratoTV3 (grant 122/C/2015) and "la Caixa" Banking Foundation (project HR17-00247). The PESA study is co-funded equally by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, and Banco Santander, Madrid, Spain. The ILERVAS study was funded by the Diputacio de Lleida. The study also receives funding from the Instituto de Salud Carlos III (PI15/02019; PI18/00610; RD16/0009) and the FEDER funds. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacion y Universidades (MCNU) and the Pro CNIC Foundation.
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    Improved integrative analysis of the thiol redox proteome using filter-aided sample preparation
    (Elsevier, 2020-03) Bonzon-Kulichenko, Elena; Camafeita, Emilio; Lopez, Juan Antonio; Gómez-Serrano, María; Jorge, Inmaculada; Calvo, Enrique; Nunez, Estefania; Trevisan-Herraz, Marco; Bagwan, Navratan; Bárcena, José Antonio; Peral, Belén; Vazquez, Jesus; Ministerio de Ciencia, Innovación y Universidades (España); Ministerio de Economía, Industria y Competitividad (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Fundación La Caixa; Fundación La Marató TV3; Fundación ProCNIC
    Changes in the oxidation state of protein Cys residues are involved in cell signalling and play a key role in a variety of pathophysiological states. We had previously developed GELSILOX, an in-gel method that enables the large-scale, parallel analysis of dynamic alterations to the redox state of Cys sites and protein abundance changes. Here we present FASILOX, a further development of the GELSILOX approach featuring: i) significantly increased peptide recovery, ii) enhanced sensitivity for the detection of Cys oxidative alterations, and iii) streamlined workflow that results in shortened assay duration. In mitochondria isolated from the adipose tissue of obese, diabetic patients, FASILOX revealed a sexually dimorphic trait of Cys oxidation involving mainly mitochondrial oxidative phosphorylation complexes. These results provide the first evidence for a decreased efficiency in the antioxidant response of men as compared to women.
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    Genomic insights into the Ixodes scapularis tick vector of Lyme disease
    (Nature Publishing Group, 2016) Gulia-Nuss, Monika; Nuss, Andrew B.; Meyer, Jason M.; Sonenshine, Daniel E.; Roe, R. Michael; Waterhouse, Robert M.; Sattelle, David B.; de la Fuente, Jose; Ribeiro, Jose M.; Megy, Karine; Thimmapuram, Jyothi; Miller, Jason R.; Walenz, Brian P.; Koren, Sergey; Hostetler, Jessica B.; Thiagarajan, Mathangi; Joardar, Vinita S.; Hannick, Linda I.; Bidwell, Shelby; Hammond, Martin P.; Young, Sarah; Zeng, Qiandong; Abrudan, Jenica L.; Almeida, Francisca C.; Ayllon, Nieves; Bhide, Ketaki; Bissinger, Brooke W.; Bonzon-Kulichenko, Elena; Buckingham, Steven D.; Caffrey, Daniel R.; Caimano, Melissa J.; Croset, Vincent; Driscoll, Timothy; Gilbert, Don; Gillespie, Joseph J.; Giraldo-Calderon, Gloria I.; Grabowski, Jeffrey M.; Jiang, David; Khalil, Sayed M. S.; Kim, Donghun; Kocan, Katherine M.; Koci, Juraj; Kuhn, Richard J.; Kurtti, Timothy J.; Lees, Kristin; Lang, Emma G.; Kennedy, Ryan C.; Kwon, Hyeogsun; Perera, Rushika; Qi, Yumin; Radolf, Justin D.; Sakamoto, Joyce M.; Sanchez-Gracia, Alejandro; Severo, Maiara S.; Silverman, Neal; Simo, Ladislav; Tojo, Marta; Tornador, Cristian; Van Zee, Janice P.; Vazquez, Jesus; Vieira, Filipe G.; Villar, Margarita; Wespiser, Adam R.; Yang, Yunlong; Zhu, Jiwei; Arensburger, Peter; Pietrantonio, Patricia V.; Barker, Stephen C.; Shao, Renfu; Zdobnov, Evgeny M.; Hauser, Frank; Grimmelikhuijzen, Cornelis J. P.; Park, Yoonseong; Rozas, Julio; Benton, Richard; Pedra, Joao H. F.; Nelson, David R.; Unger, Maria F.; Tubio, Jose M. C.; Tu, Zhijian; Robertson, Hugh M.; Shumway, Martin; Sutton, Granger; Wortman, Jennifer R.; Lawson, Daniel; Wikel, Stephen K.; Nene, Vishvanath M.; Fraser, Claire M.; Collins, Frank H.; Birren, Bruce; Nelson, Karen E.; Caler, Elisabet; Hill, Catherine A.; NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos); National Institutes of Health (Estados Unidos); Australian Research Council; Ministerio de Ciencia e Innovación (España); United States Department of Health and Human Services; National Science Foundation (Estados Unidos); Xunta de Galicia (España); Unión Europea. Comisión Europea; United States Department of Agriculture. National Institute of Food and Agriculture; Texas AgriLife Research; Unión Europea. Comisión Europea. European Research Council (ERC); Swiss National Science Foundation; Fundação para a Ciência e Tecnologia (Portugal); Lundbeck Foundation; Broad Genomics Platform
    Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing similar to 57\% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host `questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.
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    Malondialdehyde-modified HDL particles elicit a specific IgG response in abdominal aortic aneurysm.
    (Elsevier, 2021-10) Rodríguez-Carrio, Javier; Cerro-Pardo, Isabel; Lindholt, Jes S; Bonzon-Kulichenko, Elena; Martínez-López, Diego; Roldán-Montero, Raquel; Escolà-Gil, Joan-Carles; Michel, Jean-Baptiste; Blanco-Colio, Luis Miguel; Vazquez, Jesus; Suárez, Ana; Martín-Ventura, José Luis; Ministerio de Economía, Innovación y Competitividad (España); Comunidad de Madrid (España); Instituto de Salud Carlos III; Fundación La Caixa
    High Density Lipoprotein (HDL) plays a protective role in abdominal aortic aneurysm (AAA); however, recent findings suggest that oxidative modifications could lead to dysfunctional HDL in AAA. This study aimed at testing the effect of oxidized HDL on aortic lesions and humoral immune responses in a mouse model of AAA induced by elastase, and evaluating whether antibodies against modified HDL can be found in AAA patients. HDL particles were oxidized with malondialdehyde (HDL-MDA) and the changes were studied by biochemical and proteomics approaches. Experimental AAA was induced in mice by elastase perfusion and then mice were treated with HDL-MDA, HDL or vehicle for 14 days. Aortic lesions were studied by histomorphometric analysis. Levels of anti-HDL-MDA IgG antibodies were measured by an in-house immunoassay in the mouse model, in human tissue-supernatants and in plasma samples from the VIVA cohort. HDL oxidation with MDA was confirmed by enhanced susceptibility to diene formation. Proteomics demonstrated the presence of MDA adducts on Lysine residues of HDL proteins, mainly ApoA-I. MDA-modification of HDL abrogated the protective effect of HDL on cultured endothelial cells as well as on AAA dilation in mice. Exposure to HDL-MDA elicited an anti-HDL-MDA IgG response in mice. Anti-HDL-MDA were also detected in tissue-conditioned media from AAA patients, mainly in intraluminal thrombus. Higher plasma levels of anti-HDL-MDA IgG antibodies were found in AAA patients compared to controls. Anti-HDL-MDA levels were associated with smoking and were independent predictors of overall mortality in AAA patients. Overall, MDA-oxidized HDL trigger a specific humoral immune response in mice. Besides, antibodies against HDL-MDA can be detected in tissue and plasma of AAA patients, suggesting its potential use as surrogate stable biomarkers of oxidative stress in AAA.
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    The chaperonin CCT controls T cell receptor-driven 3D configuration of centrioles.
    (American Association for the Advancement of Science (AAAS), 2020-12) Martin-Cofreces, Noa B.; Chichon, F J; Calvo, Enrique; Torralba, Daniel; Bustos-Moran, Eugenio; Dosil, Sara G; Rojas-Gomez, A; Bonzon-Kulichenko, Elena; Lopez, Juan Antonio; Oton, J; Sorrentino, A; Zabala, J C; Vernos, Isabelle; Vazquez, Jesus; Valpuesta, Jose; Sanchez-Madrid, Francisco; ALBA Synchrotron; Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España); Fundación Ramón Areces; Fundación BBVA; Fundación La Marató TV3; Fundación La Caixa; Ministerio de Ciencia e Innovación (España); Fundación ProCNIC; Centro Nacional de Biotecnología (España)
    T lymphocyte activation requires the formation of immune synapses (IS) with antigen-presenting cells. The dynamics of membrane receptors, signaling scaffolds, microfilaments, and microtubules at the IS determine the potency of T cell activation and subsequent immune response. Here, we show that the cytosolic chaperonin CCT (chaperonin-containing TCP1) controls the changes in reciprocal orientation of the centrioles and polarization of the tubulin dynamics induced by T cell receptor in T lymphocytes forming an IS. CCT also controls the mitochondrial ultrastructure and the metabolic status of T cells, regulating the de novo synthesis of tubulin as well as posttranslational modifications (poly-glutamylation, acetylation, Δ1 and Δ2) of αβ-tubulin heterodimers, fine-tuning tubulin dynamics. These changes ultimately determine the function and organization of the centrioles, as shown by three-dimensional reconstruction of resting and stimulated primary T cells using cryo-soft x-ray tomography. Through this mechanism, CCT governs T cell activation and polarity.