Proteins reversibly oxidized in cysteines in endothellial cells in response to acute hypoxia

Comunicaciones a congreso

Proteómica redox diferencial: identificación de proteínas oxidadas reversiblemente en respuesta a hipoxia

Comunicaciones a congreso

Specificity in S-Nitrosylation: a short-range mechanism for NO signaling?

Significance: Nitric oxide (NO) classical and less classical signaling mechanisms (through interaction with soluble guanylate cyclase and cytochrome c oxidase, respectively) operate through direct binding of NO to protein metal centers, and rely on diffusibility of the NO molecule. S-Nitrosylation, a covalent post-translational modification of protein cysteines, has emerged as a paradigm of nonclassical NO signaling. Recent Advances: Several nonenzymatic mechanisms for S-nitrosylation formation and destruction have been described. Enzymatic mechanisms for transnitrosylation and denitrosylation have been also studied as regulators of the modification of specific subsets of proteins. The advancement of modification-specific proteomic methodologies has allowed progress in the study of diverse S-nitrosoproteomes, raising clues and questions about the parameters for determining the protein specificity of the modification. Critical Issues: We propose that S-nitrosylation is mainly a short-range mechanism of NO signaling, exerted in a relatively limited range of action around the NO sources, and tightly related to the very controlled regulation of subcellular localization of nitric oxide synthases. We review the nonenzymatic and enzymatic mechanisms that support this concept, as well as physiological examples of mammalian systems that illustrate well the precise compartmentalization of S-nitrosylation. Future Directions: Individual and proteomic studies of protein S-nitrosylation-based signaling should take into account the subcellular localization in order to gain further insight into the functional role of this modification in (patho)physiological settings. Antioxid. Redox Signal. 19, 1220-1235.Spanish Government [CSD2007-00020, CP07/00143, PS09/00101, SAF2009-7520, PI10/02136]; Spanish-Portuguese Integrated Action Grant [PRI-AIBPT-2011-1015/E-10/12]; Foundation for Science and Technology (FCT, Portugal) [PTDC/SAU-NEU/102612/2008, PTDC/SAU-NMC/112183/2009, PEst-OE/EQB/LA0023/2011]; COST action [BM1005]info:eu-repo/semantics/publishedVersio

The natural history of QTc interval and its clinical impact in coronavirus disease 2019 survivors after 1 year

Background and objectiveProlonged QTc interval on admission and a higher risk of death in SARS-CoV-2 patients have been reported. The long-term clinical impact of prolonged QTc interval is unknown. This study examined the relationship in COVID-19 survivors of a prolonged QTc on admission with long-term adverse events, changes in QTc duration and its impact on 1-year prognosis, and factors associated with a prolonged QTc at follow-up.MethodsWe conducted a single-center prospective cohort study of 523 SARS-CoV-2-positive patients who were alive on discharge. An electrocardiogram was taken on these patients within the first 48 h after diagnosis and before the administration of any medication with a known effect on QT interval and repeated in 421 patients 7 months after discharge. Mortality, hospital readmission, and new arrhythmia rates 1 year after discharge were reviewed.ResultsThirty-one (6.3%) survivors had a baseline prolonged QTc. They were older, had more cardiovascular risk factors, cardiac disease, and comorbidities, and higher levels of terminal pro-brain natriuretic peptide. There was no relationship between prolonged QTc on admission and the 1-year endpoint (9.8% vs. 5.5%, p = 0.212). In 84% of survivors with prolonged baseline QTc, it normalized at 7.9 ± 2.2 months. Of the survivors, 2.4% had prolonged QTc at follow-up, and this was independently associated with obesity, ischemic cardiomyopathy, chronic obstructive pulmonary disease, and cancer. Prolonged baseline QTc was not independently associated with the composite adverse event at 1 year.ConclusionsProlonged QTc in the acute phase normalized in most COVID-19 survivors and had no clinical long-term impact. Prolonged QTc at follow-up was related to the presence of obesity and previously acquired chronic diseases and was not related to 1-year prognosis

Identification of new targets of S-nitrosylation in neural stem cells by thiol redox proteomics

Nitric oxide (NO) is well established as a regulator of neurogenesis. NO increases the proliferation of neural stem cells (NSC), and is essential for hippocampal injury-induced neurogenesis following an excitotoxic lesion. One of the mechanisms underlying non-classical NO cell signaling is protein S-nitrosylation. This post-translational modification consists in the formation of a nitrosothiol group (R-SNO) in cysteine residues, which can promote formation of other oxidative modifications in those cysteine residues. S-nitrosylation can regulate many physiological processes, including neuronal plasticity and neurogenesis. In this work, we aimed to identify S-nitrosylation targets of NO that could participate in neurogenesis. In NSC, we identified a group of proteins oxidatively modified using complementary techniques of thiol redox proteomics. S-nitrosylation of some of these proteins was confirmed and validated in a seizure mouse model of hippocampal injury and in cultured hippocampal stem cells. The identified S-nitrosylated proteins are involved in the ERK/MAPK pathway and may be important targets of NO to enhance the proliferation of NSC.PTDC/QUI-QFI/29319/2017; UID/BIM/04773/2019info:eu-repo/semantics/publishedVersio

Informe del sismo de Lorca del 11 de mayo de 2011

En la reciente historia sísmica de España, desde el terremoto de 1956 en Albolote (Granada) con once muertos y el de 1969 al SW del Cabo San Vicente con cuatro, el terremoto de Lorca de 11 de mayo de 2011 (magnitud 5.1) ha vuelto a ser especialmente importante por haber ocasionado nueve víctimas mortales. El movimiento sísmico, localizado muy próximo a la ciudad de Lorca, ha afectado directamente a más de 90.000 personas, que han sufrido sus consecuencias al registrarse con una intensidad de grado VII en la escala europea EMS, lo que ha motivado daños notables en las viviendas. El presente informe trata de reflejar las características del terremoto y de su serie de réplicas, recogiendo los trabajos que han desarrollado diferentes equipos de investigación, tanto previos al terremoto como posteriores. El estudio describe los aspectos científicos y técnicos de mayor interés, desde la historia sísmica de la zona hasta el comportamiento de las edificaciones de la ciudad de Lorca. Asimismo, se acompaña de un encuadre geológico de la zona y de las características de la falla de Alhama de Murcia, responsable de la ocurrencia del terremoto. Como consecuencia de los terremotos que hubo la misma zona en el año 2005, precedidos por un apreciable nivel de actividad sísmica en los años 1999 y 2002, la región de Murcia fue objeto del proyecto RISMUR, cofinanciado por el Instituto Geográfico Nacional y en el que participaron los redactores de este informe. Algunos de los aspectos de este proyecto, en concreto los relativos a la peligrosidad sísmica han sido incluidos, incidiendo en los resultados que se obtuvieron en la ciudad de Lorca. El informe va acompañado al final de una serie de conclusiones en relación con cada uno de los temas tratados, resaltando aquellos aspectos que se deberán tener en cuenta en futuros proyectos, a fin de mejorar por un lado el conocimiento de la sismicidad y peligrosidad sísmica y por otro para la adecuación de la normativa sismorresistente.Peer reviewe

Regulation of SCF TIR1/AFB E3 ligase assembly by S-nitrosylation of Arabidopsis SKP1-like1 impacts on auxin signaling

The F-box proteins (FBPs) TIR1/AFBs are the substrate recognition subunits of SKP1–cullin–F-box (SCF) ubiquitin ligase complexes and together with Aux/IAAs form the auxin co-receptor. Although tremendous knowledge on auxin perception and signaling has been gained in the last years, SCFTIR1/AFBs complex assembly and stabilization are emerging as new layers of regulation. Here, we investigated how nitric oxide (NO), through S-nitrosylation of ASK1 is involved in SCFTIR1/AFBs assembly. We demonstrate that ASK1 is S-nitrosylated and S-glutathionylated in cysteine (Cys) 37 and Cys118 residues in vitro. Both, in vitro and in vivo protein-protein interaction assays show that NO enhances ASK1 binding to CUL1 and TIR1/AFB2, required for SCFTIR1/AFB2 assembly. In addition, we demonstrate that Cys37 and Cys118 are essential residues for proper activation of auxin signaling pathway in planta. Phylogenetic analysis revealed that Cys37 residue is only conserved in SKP proteins in Angiosperms, suggesting that S-nitrosylation on Cys37 could represent an evolutionary adaption for SKP1 function in flowering plants. Collectively, these findings indicate that multiple events of redox modifications might be part of a fine-tuning regulation of SCFTIR1/AFBs for proper auxin signal transduction.This work has been supported by grants from CONICET (PIP 0202 to M.C.T), Universidad Nacional de Mar del Plata and Agencia Nacional de Promoción Científica y Tecnológica, -Argentina (PICT 1167 to M.C.T and PICT 2421 to C.A.C); from the Spanish Government (PS09/00101 and PI12/00875 to A.M.R., cofinanced by the European Union ERDF), and by the Argentinian-Spanish Integrated Action ES/11/02 / PRIAIBAR- 2011-0782. A.M.R. is supported by the I3SNS programme (ISCIII, Spanish Government). The Proteomics Service of the CBMSO is a member of Proteored (PRB2-ISCIII), and is supported by grants PT13/ 0001/0024 and PT17/0019/0018 of Spanish Government (cofinanced by the European Union ERDF). Work in the laboratory of M.E is supported by grants from the National Institutes of Health (NIH) GM43644, The Howard Hughes Medical Institute and the Gordon and Betty Moore Foundation, US