RESUMO
Intracellular pathogens pose a significant threat to animals. In defense, innate immune sensors attempt to detect these pathogens using pattern recognition receptors that either directly detect microbial molecules or indirectly detect their pathogenic activity. These sensors trigger different forms of regulated cell death, including pyroptosis, apoptosis, and necroptosis, which eliminate the infected host cell niche while simultaneously promoting beneficial immune responses. These defenses force intracellular pathogens to evolve strategies to minimize or completely evade the sensors. In this review, we discuss recent advances in our understanding of the cytosolic pattern recognition receptors that drive cell death, including NLRP1, NLRP3, NLRP6, NLRP9, NLRC4, AIM2, IFI16, and ZBP1.
Assuntos
Inflamassomos , Piroptose , Animais , Apoptose , Morte Celular , Humanos , Inflamassomos/metabolismo , NecroptoseRESUMO
Inflammasomes are inflammatory signaling complexes that provide molecular platforms to activate the protease function of inflammatory caspases. Caspases-1, -4, -5, and -11 are inflammatory caspases activated by inflammasomes to drive lytic cell death and inflammatory mediator production, thereby activating host-protective and pathological immune responses. Here, we comprehensively review the mechanisms that govern the activity of inflammatory caspases. We discuss inflammatory caspase activation and deactivation mechanisms, alongside the physiological importance of caspase activity kinetics. We also examine mechanisms of caspase substrate selection and how inflammasome and cell identities influence caspase activity and resultant inflammatory and pyroptotic cellular programs. Understanding how inflammatory caspases are regulated may offer new strategies for treating infection and inflammasome-driven disease.
Assuntos
Caspases , Inflamassomos , Animais , Caspase 1/metabolismo , Caspases/metabolismo , Morte Celular , Humanos , Inflamassomos/metabolismo , PiroptoseRESUMO
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.
Assuntos
Apoptose , Animais , Morte Celular , Homeostase , HumanosRESUMO
Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D-induced pyroptosis.
Assuntos
Caspases/metabolismo , Morte Celular , Inflamação/etiologia , Inflamação/metabolismo , Proteínas de Neoplasias/genética , Piroptose/genética , Animais , Apoptose , Biomarcadores , Caspases/genética , Morte Celular/genética , Suscetibilidade a Doenças , Ativação Enzimática , Humanos , Inflamação/patologia , Proteínas de Neoplasias/metabolismo , Transdução de SinaisRESUMO
It is difficult to believe that in about 1960 practically nothing was known about the thymus and some of its products, T cells bearing αß receptors for antigen. Thus I was lucky to join the field of T cell biology almost at its beginning, when knowledge about the cells was just getting off the ground and there was so much to discover. This article describes findings about these cells made by others and myself that led us all from ignorance, via complete confusion, to our current state of knowledge. I believe I was fortunate to practice science in very supportive institutions and with very collaborative colleagues in two countries that both encourage independent research by independent scientists, while simultaneously ignoring or somehow being able to avoid some of the difficulties of being a woman in what was, at the time, a male-dominated profession.
Assuntos
Suscetibilidade a Doenças , Transtorno Obsessivo-Compulsivo/etiologia , Transtorno Obsessivo-Compulsivo/metabolismo , Animais , Autoimunidade , Biomarcadores , Morte Celular , Citocinas/metabolismo , Suscetibilidade a Doenças/imunologia , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/imunologia , Antígenos de Histocompatibilidade/metabolismo , Humanos , Imunidade Inata , Transtorno Obsessivo-Compulsivo/psicologia , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Superantígenos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timo/imunologia , Timo/metabolismoRESUMO
The human body generates 10-100 billion cells every day, and the same number of cells die to maintain homeostasis in our body. Cells infected by bacteria or viruses also die. The cell death that occurs under physiological conditions mainly proceeds by apoptosis, which is a noninflammatory, or silent, process, while pathogen infection induces necroptosis or pyroptosis, which activates the immune system and causes inflammation. Dead cells generated by apoptosis are quickly engulfed by macrophages for degradation. Caspases are a large family of cysteine proteases that act in cascades. A cascade that leads to caspase 3 activation mediates apoptosis and is responsible for killing cells, recruiting macrophages, and presenting an "eat me" signal(s). When apoptotic cells are not efficiently engulfed by macrophages, they undergo secondary necrosis and release intracellular materials that represent a damage-associated molecular pattern, which may lead to a systemic lupus-like autoimmune disease.
Assuntos
Apoptose/imunologia , Fagocitose/imunologia , Animais , Biomarcadores , Caspases/metabolismo , Morte Celular , Humanos , Lisossomos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Fosfatidilserinas/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Receptores de Morte Celular/metabolismo , Transdução de Sinais , Especificidade por SubstratoRESUMO
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.
Assuntos
Morte Celular , Transdução de Sinais , Humanos , Apoptose , Ferroptose , Homeostase , PiroptoseRESUMO
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.
Assuntos
Morte Celular , Humanos , Apoptose , Caspases/metabolismo , Células HEK293 , Proteólise , Piroptose/efeitos dos fármacos , Biologia Sintética/métodos , Células CultivadasRESUMO
While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also damages RNA, triggering transcriptome-wide ribosomal collisions and eliciting a ribotoxic stress response (RSR). However, the relative contributions, timing, and regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, and biochemical approaches to create a chronological atlas of signaling events activated in cells responding to UV damage. We discover that UV-induced apoptosis is mediated by the RSR kinase ZAK and not through the DDR. We identify two negative-feedback modules that regulate ZAK-mediated apoptosis: (1) GCN2 activation limits ribosomal collisions and attenuates ZAK-mediated RSR and (2) ZAK activity leads to phosphodegron autophosphorylation and its subsequent degradation. These events tune ZAK's activity to collision levels to establish regimes of homeostasis, tolerance, and death, revealing its key role as the cellular sentinel for nucleic acid damage.
Assuntos
Apoptose , Dano ao DNA , Raios Ultravioleta , Raios Ultravioleta/efeitos adversos , Apoptose/efeitos da radiação , Fosforilação/efeitos da radiação , Humanos , Transdução de Sinais/efeitos da radiação , Proteínas Serina-Treonina Quinases/metabolismo , Estresse Fisiológico/efeitos da radiação , Ribossomos/metabolismo , Morte Celular/efeitos da radiaçãoRESUMO
Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs.
Assuntos
Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/patologia , Proteostase , Agregação Patológica de Proteínas/metabolismo , Morte Celular , Citoesqueleto/metabolismoRESUMO
Inflammasomes are critical sentinels of the innate immune system that respond to threats to the host through recognition of distinct molecules, known as pathogen- or damage-associated molecular patterns (PAMPs/DAMPs), or disruptions of cellular homeostasis, referred to as homeostasis-altering molecular processes (HAMPs) or effector-triggered immunity (ETI). Several distinct proteins nucleate inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRC4/NAIP, AIM2, pyrin, and caspases-4/-5/-11. This diverse array of sensors strengthens the inflammasome response through redundancy and plasticity. Here, we present an overview of these pathways, outlining the mechanisms of inflammasome formation, subcellular regulation, and pyroptosis, and discuss the wide-reaching effects of inflammasomes in human disease.
Assuntos
Inflamassomos , Humanos , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspases/metabolismo , Morte Celular , Inflamassomos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PiroptoseRESUMO
Cell proliferation and cell death are integral elements in maintaining homeostatic balance in metazoans. Disease pathologies ensue when these processes are disturbed. A plethora of evidence indicates that malfunction of cell death can lead to inflammation, autoimmunity, or immunodeficiency. Programmed necrosis or necroptosis is a form of nonapoptotic cell death driven by the receptor interacting protein kinase 3 (RIPK3) and its substrate, mixed lineage kinase domain-like (MLKL). RIPK3 partners with its upstream adaptors RIPK1, TRIF, or DAI to signal for necroptosis in response to death receptor or Toll-like receptor stimulation, pathogen infection, or sterile cell injury. Necroptosis promotes inflammation through leakage of cellular contents from damaged plasma membranes. Intriguingly, many of the signal adaptors of necroptosis have dual functions in innate immune signaling. This unique signature illustrates the cooperative nature of necroptosis and innate inflammatory signaling pathways in managing cell and organismal stresses from pathogen infection and sterile tissue injury.
Assuntos
Inflamação/metabolismo , Inflamação/patologia , Necrose/metabolismo , Transdução de Sinais , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/metabolismo , Infecções Bacterianas/patologia , Evolução Biológica , Morte Celular , Humanos , Inflamassomos/metabolismo , Inflamação/genética , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Doenças Parasitárias/genética , Doenças Parasitárias/metabolismo , Doenças Parasitárias/patologia , Fosforilação , Ligação Proteica , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ubiquitinação , Viroses/genética , Viroses/metabolismo , Viroses/patologiaRESUMO
Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, was identified as a distinct phenomenon and named a decade ago. Ferroptosis has been implicated in a broad set of biological contexts, from development to aging, immunity, and cancer. This review describes key regulators of this form of cell death within a framework of metabolism, ROS biology, and iron biology. Key concepts and major unanswered questions in the ferroptosis field are highlighted. The next decade promises to yield further breakthroughs in the mechanisms governing ferroptosis and additional ways of harnessing ferroptosis for therapeutic benefit.
Assuntos
Ferroptose , Morte Celular , Ferro/metabolismo , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Plant immune receptors often contain TIR domains, which can oligomerize to form active enzyme complexes in response to pathogen infections. In this issue of Cell, Yu and colleagues discover that some plant TIR domains possess a novel 2',3'-cAMP/cGMP synthetase activity that cleaves double-stranded RNA/DNA, triggering cell death during plant immune responses.
Assuntos
Imunidade Vegetal , Receptores Imunológicos , Morte Celular/genética , Imunidade Vegetal/genética , Plantas/metabolismo , Receptores Imunológicos/metabolismoRESUMO
2',3'-cAMP is a positional isomer of the well-established second messenger 3',5'-cAMP, but little is known about the biology of this noncanonical cyclic nucleotide monophosphate (cNMP). Toll/interleukin-1 receptor (TIR) domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors have the NADase function necessary but insufficient to activate plant immune responses. Here, we show that plant TIR proteins, besides being NADases, act as 2',3'-cAMP/cGMP synthetases by hydrolyzing RNA/DNA. Structural data show that a TIR domain adopts distinct oligomers with mutually exclusive NADase and synthetase activity. Mutations specifically disrupting the synthetase activity abrogate TIR-mediated cell death in Nicotiana benthamiana (Nb), supporting an important role for these cNMPs in TIR signaling. Furthermore, the Arabidopsis negative regulator of TIR-NLR signaling, NUDT7, displays 2',3'-cAMP/cGMP but not 3',5'-cAMP/cGMP phosphodiesterase activity and suppresses cell death activity of TIRs in Nb. Our study identifies a family of 2',3'-cAMP/cGMP synthetases and establishes a critical role for them in plant immune responses.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Morte Celular/genética , AMP Cíclico/biossíntese , GMP Cíclico/biossíntese , Ligases/metabolismo , NAD+ Nucleosidase/metabolismo , Doenças das Plantas , Imunidade Vegetal/fisiologia , Proteínas de Plantas/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Interleucina-1/metabolismo , Nicotiana/genética , Nicotiana/metabolismoRESUMO
The persistence of CD4+ T cells carrying latent human immunodeficiency virus-1 (HIV-1) proviruses is the main barrier to a cure. New therapeutics to enhance HIV-1-specific immune responses and clear infected cells will probably be necessary to achieve reduction of the latent reservoir. In the present study, we report two single-chain diabodies (scDbs) that target the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16). We show that the scDbs promoted robust and HIV-1-specific natural killer (NK) cell activation and NK cell-mediated lysis of infected cells. Cocultures of CD4+ T cells from people with HIV-1 on antiretroviral therapy (ART) with autologous NK cells and the scDbs resulted in marked elimination of reservoir cells that was dependent on latency reversal. Treatment of human interleukin-15 transgenic NSG mice with one of the scDbs after ART initiation enhanced NK cell activity and reduced reservoir size. Thus, HIV-1-specific scDbs merit further evaluation as potential therapeutics for clearance of the latent reservoir.
Assuntos
Anticorpos Biespecíficos , HIV-1 , Animais , Camundongos , Humanos , Células Matadoras Naturais , Citotoxicidade Imunológica , Morte Celular , Camundongos TransgênicosRESUMO
Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.
Assuntos
Morte Celular , Animais , Humanos , Apoptose/fisiologia , Caspases/metabolismo , Morte Celular/fisiologia , Ferroptose/fisiologia , Lisossomos/metabolismo , Necroptose , Piroptose/fisiologia , Transdução de SinaisRESUMO
In this issue of Cell, Evavold et al. (2021) report that mTOR Complex 1 (mTORC1), a metabolic signaling complex, controls reactive oxygen species (ROS) production in mitochondria, which in turn promotes inflammatory cell death mediated by gasdermin D (GSDMD). This provides a new mechanistic connection between metabolic signaling and inflammatory cell death.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Piroptose , Morte Celular , Proteínas de Ligação a Fosfato , Transdução de SinaisRESUMO
Plant intracellular NLR proteins detect pathogen effectors and then form multimeric protein complexes ("resistosomes") that activate immune responses and cell death through unknown mechanisms. In this issue of Cell, Bi et al. show that the ZAR1 resistosome exhibits cation channel activity, enabling calcium influx that activates defense mechanisms and culminates in cell death.
Assuntos
Proteínas NLR , Imunidade Vegetal , Morte Celular , Plantas , Transdução de SinaisRESUMO
Many enveloped viruses require the endosomal sorting complexes required for transport (ESCRT) pathway to exit infected cells. This highly conserved pathway mediates essential cellular membrane fission events, which restricts the acquisition of adaptive mutations to counteract viral co-option. Here, we describe duplicated and truncated copies of the ESCRT-III factor CHMP3 that block ESCRT-dependent virus budding and arose independently in New World monkeys and mice. When expressed in human cells, these retroCHMP3 proteins potently inhibit release of retroviruses, paramyxoviruses, and filoviruses. Remarkably, retroCHMP3 proteins have evolved to reduce interactions with other ESCRT-III factors and have little effect on cellular ESCRT processes, revealing routes for decoupling cellular ESCRT functions from viral exploitation. The repurposing of duplicated ESCRT-III proteins thus provides a mechanism to generate broad-spectrum viral budding inhibitors without blocking highly conserved essential cellular ESCRT functions.