Desvelando el curso evolutivo de la red de proteínas que interaccionan con el Citocromo C en la muerte celular programada

La organización celular de los organismos fue descubierta a mediados del siglo XIX por Schwann y Schleiden (1847). Poco tiempo después se puso de manifiesto que la muerte celular representaba una parte esencial del desarrollo animal (Vogt, 1884). Observada en primer lugar durante la metamorfosis de los anfibios (Vogt, 1884), pronto se puso de manifiesto que la muerte celular ocurría de forma normal en el desarrollo de muchos tejidos, tanto en vertebrados como en invertebrados (Glucksmann, 1951; Clarke y Clarke, 1996). Posteriormente, se descubrió que el uso de inhibidores de la síntesis de ARN o de proteínas, inhibía la muerte celular que ocurría durante la metamorfosis tanto de anfibios (Tata, 1966) como de insectos (Lockshin, 1969), indicando que la muerte celular requería de la síntesis macromolecular, siendo, por lo tanto, un proceso controlado a nivel celular. El término muerte celular programada (PCD, del inglés, Programmed Cell Death) fue inicialmente usado para describir la muerte celular que ocurría en sitios y momentos predecibles durante el desarrollo de los organismos (Lockshin y Williams, 1969). Sin embargo, quedaba claro que algunos de estos eventos de muerte celular podían ser prevenidos por sustancias liberadas por otros tejidos, indicando que estas muertes no eran inevitables y podían ser suprimidas mediante señales provenientes de otras células (Saunders, 1966). En 1972, Kerr, Wyllie y Currie (Kerr et al., 1972), reunieron una serie de evidencias experimentales, tanto propias como ajenas, con las que consiguieron establecer una clara separación entre la muerte celular que ocurre durante la homeostasis y el desarrollo tisular y aquella que se produce en sitios de lesiones agudas. En el segundo caso, las células y sus orgánulos tienden a hincharse y reventar en un proceso conocido como necrosis celular, el cual implica la liberación del contenido celular, lo que, normalmente, induce una respuesta inflamatoria. Por el contrario, cuando las células mueren durante el desarrollo, o como consecuencia de la homeostasis celular, frecuentemente se observa tanto encogimiento celular como condensación citoplásmica, mientras que tanto los orgánulos como la membrana plasmática mantienen su integridad en un proceso que Kerr y colaboradores denominaron apoptosis (del griego, apó: separación y ptôsis: caída). A diferencia de lo que sucede durante la necrosis, en la apoptosis las células muertas o sus fragmentos son fagocitados por las células vecinas o por macrófagos, antes de que se produzca la liberación de los contenidos intracelulares, evitándose de este modo una respuesta inflamatoria. Kerr y colaboradores constataron que la muerte celular apoptótica es muy similar en tejidos y organismos diferentes, por lo que propusieron que este fenómeno reflejaba la existencia de un programa activo e intracelular de muerte celular, que podía ser activado o inhibido por diferentes estímulos, tanto fisiológicos como patológicos. A pesar de ello, la aceptación de la existencia de un proceso de PCD llevó más de 20 años y fue posible, principalmente, gracias a estudios genéticos llevados a cabo en Caenorhabditis elegans (C. elegans), un gusano de no más de 1 mm de longitud. Estos estudios (Horvitz et al., 1982; Ellis y Horvitz, 1986) permitieron la identificación de genes dedicados al proceso de la PCD, así como a su control. Esto se vio finalmente apoyado por el descubrimiento de que algunos de estos genes eran homólogos a genes de mamíferos (Yuan et al., 1993; Hengartner y Horvitz, 1994). Con esta aceptación, el término PCD ha pasado a tener un significado diferente al original. Ahora se emplea generalmente para referirse a cualquier tipo de muerte celular mediada por un programa intracelular, sin importar qué lo provoca y si presenta o no todas las características que describen la apoptosis (Jacobson et al., 1997)

Lysosomes: multifunctional compartments ruled by a complex regulatory network

17 p.More than 50 years have passed since Nobel laureate Cristian de Duve described for the first time the presence of tiny subcellular compartments filled with hydrolytic enzymes: the lysosome. For a long time, lysosomes were deemed simple waste bags exerting a plethora of hydrolytic activities involved in the recycling of biopolymers, and lysosomal genes were considered to just be simple housekeeping genes, transcribed in a constitutive fashion. However, lysosomes are emerging as multifunctional signalling hubs involved in multiple aspects of cell biology, both under homeostatic and pathological conditions. Lysosomes are involved in the regulation of cell metabolism through the mTOR/TFEB axis. They are also key players in the regulation and onset of the immune response. Furthermore, it is becoming clear that lysosomal hydrolases can regulate several biological processes outside of the lysosome. They are also implicated in a complex communication network among subcellular compartments that involves intimate organelle-to-organelle contacts. Furthermore, lysosomal dysfunction is nowadays accepted as the causative event behind several human pathologies: low frequency inherited diseases, cancer, or neurodegenerative, metabolic, inflammatory, and autoimmune diseases. Recent advances in our knowledge of the complex biology of lysosomes have established them as promising therapeutic targets for the treatment of different pathologies. Although recent discoveries have started to highlight that lysosomes are controlled by a complex web of regulatory networks, which in some cases seem to be cell- and stimuli-dependent, to harness the full potential of lysosomes as therapeutic targets, we need a deeper understanding of the little-known signalling pathways regulating this subcellular compartment and its functions.This work was supported by “Project PGC2018-096049-B-I00, financiado por: FEDER/Ministerio de Ciencia eI Innovación—Agencia Estatal de Investigación”. This work was also supported by the Regional Government of Andalusia (BIO198, US-1254317 US/JUNTA/FEDER, UE, US-1257019 US/JUNTA/FEDER/UE, P18-FR-3487 and P18-HO-5091) and the Ramón Areces Foundation (2021-2023). JMF is supported by an EU Marie Skłodowska Curie Action (MSCA) Individual Fellowship (CytoLysoReg101025429). We extend our thanks to Dr. Reyes Sanles Falagan for critical reading of the manuscript.Peer reviewe

A common signalosome for programmed cell death in humans and plants

Peer reviewe

A Counter-example to the mismatched decoding converse for binary-input discrete memoryless channels

This paper studies the mismatched decoding problem for binary-input discrete memoryless channels. An example is provided for which an achievable rate based on superposition coding exceeds the Csiszár-Körner-Hui rate, thus providing a counter-example to a previously reported converse result. Both numerical evaluations and theoretical results are used in establishing this claim.This work was supported in part by the European Union Seventh Framework Programme under Grant 303633, in part by the European Research Council under Grant 259663, in part by the Spanish Ministry of Economy and Competitiveness under Grant RYC-2011-08150 and Grant TEC2012-38800-C03-03, and in part by the Israel Science Foundation under Grant 2013/919

Biointeractomic scaffold hovering over apoptotic cytrochrome c

1 página.The role of cytochrome c in apoptosis is well-established, but its participation in signaling pathways in vivo remains still poorly understood due to its essential role in mitochondrial respiration.Peer reviewe

New Arabidopsis thaliana cytochrome c partners: A look into the elusive role of cytochrome c in programmed cell death in plants

Programmed cell death is an event displayed by many different organisms along the evolutionary scale. In plants, programmed cell death is necessary for development and the hypersensitive response to stress or pathogenic infection. A common feature in programmed cell death across organisms is the translocation of cytochrome c from mitochondria to the cytosol. To better understand the role of cytochrome c in the onset of programmed cell death in plants, a proteomic approach was developed based on affinity chromatography and using Arabidopsis thaliana cytochrome c as bait. Using this approach, ten putative new cytochrome c partners were identified. Of these putative partners and as indicated by bimolecular fluorescence complementation, nine of them bind the heme protein in plant protoplasts and human cells as a heterologous system. The in vitro interaction between cytochrome c and such soluble cytochrome c-targets was further corroborated using surface plasmon resonance. Taken together, the results obtained in the study indicate that Arabidopsis thaliana cytochrome c interacts with several distinct proteins involved in protein folding, translational regulation, cell death, oxidative stress, DNA damage, energetic metabolism and mRNA metabolism. Interestingly, some of these novel Arabidopsis thaliana cytochrome c-targets are closely related to those for Homo sapiens cytochrome c (Martínez-Fábregas et al., unpublished). These results indicate that the evolutionarily well-conserved cytosolic cytochrome c, appearing in organisms from plants to mammals, interacts with a wide range of targets upon programmed cell death. The data have been deposited to the ProteomeXchange with identifier PXD000280Peer reviewe

Structural and Functional Analysis of Novel Human Cytochrome c Targets in Apoptosis

Since the first description of apoptosis four decades ago, great efforts have been made to elucidate, both in vivo and in vitro, the molecular mechanisms involved in its regulation. Although the role of cytochrome c during apoptosis is well-established, relatively little is known about its participation in signaling pathways in vivo due to its essential role during respiration. To better understand the role of cytochrome c in the onset of apoptosis, a proteomic approach based on affinity chromatography with cytochrome c as bait was used in this study. In this approach, novel cytochrome c interaction partners were identified whose in vivo interaction, as well as cellular localization, were facilitated through bimolecular fluorescence complementation. Modeling of the complexes interface between cytochrome c and its counterparts indicated the involvement of the surface surrounding the heme crevice of cytochrome c, in agreement with the vast majority of known redox adducts of cytochrome c. However, in contrast to the high turnover rate of the mitochondrial cytochrome c redox adducts, those occurring under apoptosis lead to the formation of stable nucleo-cytoplasmic ensembles, as inferred mainly from surface plasmon resonance and nuclear magnetic resonance measurements, which have permitted us to corroborate the formation of such complexes in vitro. The results obtained suggest that human cytochrome c interacts with pro-survival, anti-apoptotic proteins following its release into the cytoplasm. Thus, cytochrome c may interfere with cell survival pathways and unlock apoptosis in order to prevent the spatial and temporal co-existence of antagonist signals.Peer reviewe

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

International audienceThe 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