RESUMEN
The COVID-19 pandemic was caused by the recently emerged ß-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.
Asunto(s)
COVID-19 , Inmunidad Innata , SARS-CoV-2 , Humanos , COVID-19/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/fisiología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/metabolismo , Animales , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/prevención & control , Evasión InmuneRESUMEN
Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.
Asunto(s)
Interferones , Lupus Eritematoso Sistémico , Humanos , Animales , Interferones/uso terapéutico , Linfocitos B , Linfocitos T Colaboradores-Inductores , AutoanticuerposRESUMEN
Nearly all animal cells contain proteins evolved to trigger the destruction of the cell in which they reside. The activation of these proteins occurs via sequential programs, and much effort has been expended in delineating the molecular mechanisms underlying the resulting processes of programmed cell death (PCD). These efforts have led to the definition of apoptosis as a form of nonimmunogenic PCD that is required for normal development and tissue homeostasis, and of pyroptosis and necroptosis as forms of PCD initiated by pathogen infection that are associated with inflammation and immune activation. While this paradigm has served the field well, numerous recent studies have highlighted cross talk between these programs, challenging the idea that apoptosis, pyroptosis, and necroptosis are linear pathways with defined immunological outputs. Here, we discuss the emerging idea of cell death as a signaling network, considering connections between cell death pathways both as we observe them now and in their evolutionary origins. We also discuss the engagement and subversion of cell death pathways by pathogens, as well as the key immunological outcomes of these processes.
Asunto(s)
Necroptosis , Piroptosis , Animales , Apoptosis , Humanos , Inflamación , Transducción de SeñalRESUMEN
Programmed cell death (PCD) is a requisite feature of development and homeostasis but can also be indicative of infections, injuries, and pathologies. In concordance with these heterogeneous contexts, an array of disparate effector responses occur downstream of cell death and its clearance-spanning tissue morphogenesis, homeostatic turnover, host defense, active dampening of inflammation, and tissue repair. This raises a fundamental question of how a single contextually appropriate response ensues after an event of PCD. To explore how complex inputs may together tailor the specificity of the resulting effector response, here we consider (a) the varying contexts during which different cell death modalities are observed, (b) the nature of the information that can be passed on by cell corpses, and (c) the ways by which efferocyte populations synthesize signals from dying cells with those from the surrounding microenvironment.
Asunto(s)
Apoptosis , Animales , Muerte Celular , Homeostasis , HumanosRESUMEN
Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed suicide mechanisms of apoptosis, necroptosis, and pyroptosis, or it can be a consequence of dysregulated metabolism, as in ferroptosis. Here, we review the signaling mechanisms underlying each cell-death pathway, discuss how impaired or excessive activation of the distinct cell-death processes can promote disease, and highlight existing and potential therapies for redressing imbalances in cell death in cancer and other diseases.
Asunto(s)
Muerte Celular , Transducción de Señal , Humanos , Apoptosis , Ferroptosis , Homeostasis , PiroptosisRESUMEN
Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS.
Asunto(s)
Inflamación , Proteínas de la Membrana , Esclerosis Múltiple , Neuronas , Animales , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Proteínas de la Membrana/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratones , Humanos , Inflamación/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Transducción de Señal , Autofagia , Ratones Endogámicos C57BL , Ácido Glutámico/metabolismo , Ferroptosis , Modelos Animales de Enfermedad , Femenino , MasculinoRESUMEN
Natural cell death pathways such as apoptosis and pyroptosis play dual roles: they eliminate harmful cells and modulate the immune system by dampening or stimulating inflammation. Synthetic protein circuits capable of triggering specific death programs in target cells could similarly remove harmful cells while appropriately modulating immune responses. However, cells actively influence their death modes in response to natural signals, making it challenging to control death modes. Here, we introduce naturally inspired "synpoptosis" circuits that proteolytically regulate engineered executioner proteins and mammalian cell death. These circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. Furthermore, synpoptosis circuits can be transmitted intercellularly, offering a foundation for engineering synthetic killer cells that induce desired death programs in target cells without self-destruction. Together, these results lay the groundwork for programmable control of mammalian cell death.
Asunto(s)
Muerte Celular , Humanos , Apoptosis , Caspasas/metabolismo , Células HEK293 , Proteolisis , Piroptosis/efectos de los fármacos , Biología Sintética/métodos , Células CultivadasRESUMEN
The membrane protein NINJ1 mediates plasma membrane rupture in pyroptosis and other lytic cell death pathways. Here, we report the cryo-EM structure of a NINJ1 oligomer segmented from NINJ1 rings. Each NINJ1 subunit comprises amphipathic (âº1, âº2) and transmembrane (TM) helices (âº3, âº4) and forms a chain of subunits, mainly by the TM helices and âº1. âº3 and âº4 are kinked, and the Gly residues are important for function. The NINJ1 oligomer possesses a concave hydrophobic side that should face the membrane and a convex hydrophilic side formed by âº1 and âº2, presumably upon activation. This structural observation suggests that NINJ1 can form membrane disks, consistent with membrane fragmentation by recombinant NINJ1. Live-cell and super-resolution imaging uncover ring-like structures on the plasma membrane that are released into the culture supernatant. Released NINJ1 encircles a membrane inside, as shown by lipid staining. Therefore, NINJ1-mediated membrane disk formation is different from gasdermin-mediated pore formation, resulting in membrane loss and plasma membrane rupture.
Asunto(s)
Moléculas de Adhesión Celular Neuronal , Membrana Celular , Microscopía por Crioelectrón , Membrana Celular/metabolismo , Humanos , Moléculas de Adhesión Celular Neuronal/metabolismo , Moléculas de Adhesión Celular Neuronal/química , Animales , Ratones , Células HEK293 , Piroptosis , Modelos Moleculares , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/química , Proteínas de Unión a Fosfato/metabolismoRESUMEN
NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated with inflammatory and infectious diseases, but little is known about its function as an innate immune sensor and cell death regulator. Therefore, we screened for NLRC5's role in response to infections, PAMPs, DAMPs, and cytokines. We identified that NLRC5 acts as an innate immune sensor to drive inflammatory cell death, PANoptosis, in response to specific ligands, including PAMP/heme and heme/cytokine combinations. NLRC5 interacted with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms similar to those in plants. Mechanistically, TLR signaling and NAD+ levels regulated NLRC5 expression and ROS production to control cell death. Furthermore, NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target.
Asunto(s)
Inflamación , Péptidos y Proteínas de Señalización Intracelular , NAD , Animales , Ratones , Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , NAD/metabolismo , Humanos , Inmunidad Innata , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Ratones Noqueados , Transducción de Señal , Células HEK293 , Inflamasomas/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Receptores Toll-Like/metabolismo , Masculino , Citocinas/metabolismo , Proteínas de Unión al CalcioRESUMEN
Cytosolic innate immune sensors are critical for host defense and form complexes, such as inflammasomes and PANoptosomes, that induce inflammatory cell death. The sensor NLRP12 is associated with infectious and inflammatory diseases, but its activating triggers and roles in cell death and inflammation remain unclear. Here, we discovered that NLRP12 drives inflammasome and PANoptosome activation, cell death, and inflammation in response to heme plus PAMPs or TNF. TLR2/4-mediated signaling through IRF1 induced Nlrp12 expression, which led to inflammasome formation to induce maturation of IL-1ß and IL-18. The inflammasome also served as an integral component of a larger NLRP12-PANoptosome that drove inflammatory cell death through caspase-8/RIPK3. Deletion of Nlrp12 protected mice from acute kidney injury and lethality in a hemolytic model. Overall, we identified NLRP12 as an essential cytosolic sensor for heme plus PAMPs-mediated PANoptosis, inflammation, and pathology, suggesting that NLRP12 and molecules in this pathway are potential drug targets for hemolytic and inflammatory diseases.
Asunto(s)
Inflamasomas , Moléculas de Patrón Molecular Asociado a Patógenos , Animales , Ratones , Inflamasomas/metabolismo , Hemo , Inflamación , Piroptosis , Péptidos y Proteínas de Señalización IntracelularRESUMEN
Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.
Asunto(s)
Inmunoterapia , Neoplasias , Humanos , Antígeno B7-H1 , Neoplasias/tratamiento farmacológico , Ensayos Clínicos como Asunto , Inhibidores de Puntos de Control Inmunológico/administración & dosificaciónRESUMEN
Bacterial colonies composed of genetically identical individuals can diversify to yield variant cells with distinct genotypes. Variant outgrowth manifests as sectors. Here, we show that Type VI secretion system (T6SS)-driven cell death in Vibrio cholerae colonies imposes a selective pressure for the emergence of variant strains that can evade T6SS-mediated killing. T6SS-mediated cell death occurs in two distinct spatiotemporal phases, and each phase is driven by a particular T6SS toxin. The first phase is regulated by quorum sensing and drives sectoring. The second phase does not require the T6SS-injection machinery. Variant V. cholerae strains isolated from colony sectors encode mutated quorum-sensing components that confer growth advantages by suppressing T6SS-killing activity while simultaneously boosting T6SS-killing defenses. Our findings show that the T6SS can eliminate sibling cells, suggesting a role in intra-specific antagonism. We propose that quorum-sensing-controlled T6SS-driven killing promotes V. cholerae genetic diversity, including in natural habitats and during disease.
Asunto(s)
Sistemas de Secreción Tipo VI , Vibrio cholerae , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Variación Genética , Percepción de Quorum , Sistemas de Secreción Tipo VI/genética , Sistemas de Secreción Tipo VI/metabolismo , Vibrio cholerae/metabolismoRESUMEN
Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.
Asunto(s)
Oxidorreductasas Intramoleculares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Enfermedad de Parkinson , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Endonucleasas/metabolismo , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismoRESUMEN
Gasdermin B (GSDMB) belongs to a large family of pore-forming cytolysins that execute inflammatory cell death programs. While genetic studies have linked GSDMB polymorphisms to human disease, its function in the immunological response to pathogens remains poorly understood. Here, we report a dynamic host-pathogen conflict between GSDMB and the IpaH7.8 effector protein secreted by enteroinvasive Shigella flexneri. We show that IpaH7.8 ubiquitinates and targets GSDMB for 26S proteasome destruction. This virulence strategy protects Shigella from the bacteriocidic activity of natural killer cells by suppressing granzyme-A-mediated activation of GSDMB. In contrast to the canonical function of most gasdermin family members, GSDMB does not inhibit Shigella by lysing host cells. Rather, it exhibits direct microbiocidal activity through recognition of phospholipids found on Gram-negative bacterial membranes. These findings place GSDMB as a central executioner of intracellular bacterial killing and reveal a mechanism employed by pathogens to counteract this host defense system.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Interacciones Huésped-Patógeno , Células Asesinas Naturales/inmunología , Proteínas de Neoplasias/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Shigella flexneri/fisiología , Ubiquitinación , Animales , Proteínas Bacterianas/metabolismo , Cardiolipinas/metabolismo , Línea Celular , Membrana Celular/metabolismo , Femenino , Granzimas/metabolismo , Humanos , Lípido A/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Viabilidad Microbiana , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Proteolisis , Especificidad por SustratoRESUMEN
Nucleotide-binding, leucine-rich repeat receptors (NLRs) are major immune receptors in plants and animals. Upon activation, the Arabidopsis NLR protein ZAR1 forms a pentameric resistosome in vitro and triggers immune responses and cell death in plants. In this study, we employed single-molecule imaging to show that the activated ZAR1 protein can form pentameric complexes in the plasma membrane. The ZAR1 resistosome displayed ion channel activity in Xenopus oocytes in a manner dependent on a conserved acidic residue Glu11 situated in the channel pore. Pre-assembled ZAR1 resistosome was readily incorporated into planar lipid-bilayers and displayed calcium-permeable cation-selective channel activity. Furthermore, we show that activation of ZAR1 in the plant cell led to Glu11-dependent Ca2+ influx, perturbation of subcellular structures, production of reactive oxygen species, and cell death. The results thus support that the ZAR1 resistosome acts as a calcium-permeable cation channel to trigger immunity and cell death.
Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/inmunología , Arabidopsis/metabolismo , Calcio/metabolismo , Proteínas Portadoras/metabolismo , Resistencia a la Enfermedad/inmunología , Inmunidad de la Planta , Transducción de Señal , Animales , Muerte Celular , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular , Ácido Glutámico/metabolismo , Membrana Dobles de Lípidos/metabolismo , Oocitos/metabolismo , Células Vegetales/metabolismo , Multimerización de Proteína , Protoplastos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Imagen Individual de Molécula , Vacuolas/metabolismo , XenopusRESUMEN
Understanding molecular mechanisms that dictate B cell diversity is important for targeting B cells as anti-cancer treatment. Through the single-cell dissection of B cell heterogeneity in longitudinal samples of patients with breast cancer before and after neoadjuvant chemotherapy, we revealed that an ICOSL+ B cell subset emerges after chemotherapy. Using three immunocompetent mouse models, we recapitulated the subset switch of human tumor-infiltrating B cells during chemotherapy. By employing B-cell-specific deletion mice, we showed that ICOSL in B cells boosts anti-tumor immunity by enhancing the effector to regulatory T cell ratio. The signature of ICOSL+ B cells is imprinted by complement-CR2 signaling, which is triggered by immunogenic cell death. Moreover, we identified that CD55, a complement inhibitory protein, determines the opposite roles of B cells in chemotherapy. Collectively, we demonstrated a critical role of the B cell subset switch in chemotherapy response, which has implications in designing novel anti-cancer therapies. VIDEO ABSTRACT.
Asunto(s)
Linfocitos B/inmunología , Neoplasias de la Mama/inmunología , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Animales , Antineoplásicos/metabolismo , Linfocitos B/metabolismo , Antígenos CD55/inmunología , Antígenos CD55/metabolismo , Línea Celular Tumoral , Proteínas del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Ligando Coestimulador de Linfocitos T Inducibles/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Complemento 3d/inmunología , Receptores de Complemento 3d/metabolismo , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
The pyroptosis execution protein GSDMD is cleaved by inflammasome-activated caspase-1 and LPS-activated caspase-11/4/5. The cleavage unmasks the pore-forming domain from GSDMD-C-terminal domain. How the caspases recognize GSDMD and its connection with caspase activation are unknown. Here, we show site-specific caspase-4/11 autoprocessing, generating a p10 product, is required and sufficient for cleaving GSDMD and inducing pyroptosis. The p10-form autoprocessed caspase-4/11 binds the GSDMD-C domain with a high affinity. Structural comparison of autoprocessed and unprocessed capase-11 identifies a ß sheet induced by the autoprocessing. In caspase-4/11-GSDMD-C complex crystal structures, the ß sheet organizes a hydrophobic GSDMD-binding interface that is only possible for p10-form caspase-4/11. The binding promotes dimerization-mediated caspase activation, rendering a cleavage independently of the cleavage-site tetrapeptide sequence. Crystal structure of caspase-1-GSDMD-C complex shows a similar GSDMD-recognition mode. Our study reveals an unprecedented substrate-targeting mechanism for caspases. The hydrophobic interface suggests an additional space for developing inhibitors specific for pyroptotic caspases.
Asunto(s)
Inflamasomas/ultraestructura , Complejos Multiproteicos/ultraestructura , Proteínas de Unión a Fosfato/ultraestructura , Piroptosis/genética , Animales , Caspasa 1/química , Caspasa 1/genética , Caspasa 1/ultraestructura , Caspasas Iniciadoras/química , Caspasas Iniciadoras/genética , Cristalografía por Rayos X , Células HEK293 , Células HeLa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Inflamasomas/genética , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/genética , Complejos Multiproteicos/química , Complejos Multiproteicos/genética , Proteínas de Unión a Fosfato/química , Proteínas de Unión a Fosfato/genética , Conformación Proteica en Lámina beta/genética , Dominios Proteicos/genética , Procesamiento Proteico-Postraduccional/genética , ProteolisisRESUMEN
Pathogenic and other cytoplasmic DNAs activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to induce inflammation via transcriptional activation by IRF3 and nuclear factor κB (NF-κB), but the functional consequences of exposing cGAS to chromosomes upon mitotic nuclear envelope breakdown are unknown. Here, we show that nucleosomes competitively inhibit DNA-dependent cGAS activation and that the cGAS-STING pathway is not effectively activated during normal mitosis. However, during mitotic arrest, low level cGAS-dependent IRF3 phosphorylation slowly accumulates without triggering inflammation. Phosphorylated IRF3, independently of its DNA-binding domain, stimulates apoptosis through alleviating Bcl-xL-dependent suppression of mitochondrial outer membrane permeabilization. We propose that slow accumulation of phosphorylated IRF3, normally not sufficient for inducing inflammation, can trigger transcription-independent induction of apoptosis upon mitotic aberrations. Accordingly, expression of cGAS and IRF3 in cancer cells makes mouse xenograft tumors responsive to the anti-mitotic agent Taxol. The Cancer Genome Atlas (TCGA) datasets for non-small cell lung cancer patients also suggest an effect of cGAS expression on taxane response.
Asunto(s)
Apoptosis , ADN/metabolismo , Nucleotidiltransferasas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Factor 3 Regulador del Interferón/metabolismo , Masculino , Ratones , Ratones Endogámicos NOD , Mitosis , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Neoplasias/patología , Nucleosomas/metabolismo , Nucleotidiltransferasas/antagonistas & inhibidores , Nucleotidiltransferasas/genética , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/aislamiento & purificación , Transducción de Señal , Tasa de Supervivencia , Activación Transcripcional , Proteína bcl-X/metabolismoRESUMEN
Macroautophagy (herein referred to as autophagy) is an evolutionary ancient mechanism that culminates with the lysosomal degradation of superfluous or potentially dangerous cytosolic entities. Over the past 2 decades, the molecular mechanisms underlying several variants of autophagy have been characterized in detail. Accumulating evidence suggests that most, if not all, components of the molecular machinery for autophagy also mediate autophagy-independent functions. Here, we discuss emerging data on the non-autophagic functions of autophagy-relevant proteins.
Asunto(s)
Proteínas Relacionadas con la Autofagia/metabolismo , Autofagia/fisiología , Lisosomas/metabolismo , Animales , HumanosRESUMEN
Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.