RESUMO
Maternal stress can have long-lasting epigenetic effects on offspring. To examine how epigenetic changes are triggered by stress, we examined the effects of activating the universal stress-responsive heat shock transcription factor HSF-1 in the germline of Caenorhabditis elegans. We show that, when activated in germ cells, HSF-1 recruits MET-2, the putative histone 3 lysine 9 (H3K9) methyltransferase responsible for repressive H3K9me2 (H3K9 dimethyl) marks in chromatin, and negatively bookmarks the insulin receptor daf-2 and other HSF-1 target genes. Increased H3K9me2 at these genes persists in adult progeny and shifts their stress response strategy away from inducible chaperone expression as a mechanism to survive stress and instead rely on decreased insulin/insulin growth factor (IGF-1)-like signaling (IIS). Depending on the duration of maternal heat stress exposure, this epigenetic memory is inherited by the next generation. Thus, paradoxically, HSF-1 recruits the germline machinery normally responsible for erasing transcriptional memory but, instead, establishes a heritable epigenetic memory of prior stress exposure.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Epigênese Genética , Fatores de Transcrição de Choque Térmico/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais , Somatomedinas/metabolismo , Fatores de Transcrição/genética , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Células Germinativas/metabolismo , Histonas , Insulina/metabolismo , Masculino , Meiose , Mitose , Ligação Proteica , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
During metazoan development, how cell division and metabolic programs are coordinated with nutrient availability remains unclear. Here, we show that nutrient availability signaled by the neuronal cytokine, ILC-17.1, switches Caenorhabditis elegans development between reproductive growth and dormancy by controlling the activity of the tumor suppressor p53 ortholog, CEP-1. Specifically, upon food availability, ILC-17.1 signaling by amphid neurons promotes glucose utilization and suppresses CEP-1/p53 to allow growth. In the absence of ILC-17.1, CEP-1/p53 is activated, up-regulates cell-cycle inhibitors, decreases phosphofructokinase and cytochrome C expression, and causes larvae to arrest as stress-resistant, quiescent dauers. We propose a model whereby ILC-17.1 signaling links nutrient availability and energy metabolism to cell cycle progression through CEP-1/p53. These studies describe ancestral functions of IL-17 s and the p53 family of proteins and are relevant to our understanding of neuroimmune mechanisms in cancer. They also reveal a DNA damage-independent function of CEP-1/p53 in invertebrate development and support the existence of a previously undescribed C. elegans dauer pathway.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Interleucina-17/metabolismo , Dano ao DNARESUMO
Cell-autonomous and cell-nonautonomous mechanisms of neurodegeneration appear to occur in the proteinopathies, including Alzheimer's and Parkinson's diseases. However, how neuronal toxicity is generated from misfolding-prone proteins secreted by nonneuronal tissues and whether modulating protein aggregate levels at distal locales affects the degeneration of postmitotic neurons remains unknown. We generated and characterized animal models of the transthyretin (TTR) amyloidoses that faithfully recapitulate cell-nonautonomous neuronal proteotoxicity by expressing human TTR in the Caenorhabditis elegans muscle. We identified sensory neurons with affected morphological and behavioral nociception-sensing impairments. Nonnative TTR oligomer load and neurotoxicity increased following inhibition of TTR degradation in distal macrophage-like nonaffected cells. Moreover, reducing TTR levels by RNAi or by kinetically stabilizing natively folded TTR pharmacologically decreased TTR aggregate load and attenuated neuronal dysfunction. These findings reveal a critical role for in trans modulation of aggregation-prone degradation that directly affects postmitotic tissue degeneration observed in the proteinopathies.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Pré-Albumina/metabolismo , Agregados Proteicos , Neuropatias Amiloides/genética , Neuropatias Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Humanos , Pré-Albumina/genética , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismoRESUMO
Mitochondrial functions are critical for cellular physiology; therefore, several conserved mechanisms are in place to maintain the functional integrity of mitochondria. However, many of the molecular details and components involved in ensuring mitochondrial fidelity remain obscure. Here, we identify a novel role for the conserved mitochondrial AAA ATPase Afg1 in mediating mitochondrial protein homeostasis during aging and in response to various cellular challenges. Saccharomyces cerevisiae cells lacking functional Afg1 are hypersensitive to oxidative insults, unable to tolerate protein misfolding in the matrix compartment and exhibit progressive mitochondrial failure as they age. Loss of the Afg1 ortholog LACE-1 in Caenorhabditis elegans is associated with reduced lifespan, impeded oxidative stress tolerance, impaired mitochondrial proteostasis in the motor neuron circuitry and altered behavioral plasticity. Our results indicate that Afg1 is a novel protein quality control factor, which plays an important evolutionarily conserved role in mitochondrial surveillance, and cellular and organismal health.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Caenorhabditis elegans/enzimologia , Proteostase , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Organisms function despite wide fluctuations in their environment through the maintenance of homeostasis. At the cellular level, the maintenance of proteins as functional entities at target expression levels is called protein homeostasis (or proteostasis). Cells implement proteostasis through universal and conserved quality control mechanisms that surveil and monitor protein conformation. Recent studies that exploit the powerful ability to genetically manipulate specific neurons in C. elegans have shown that cells within this metazoan lose their autonomy over this fundamental survival mechanism. These studies have uncovered novel roles for the nervous system in controlling how and when cells activate their protein quality control mechanisms. Here we discuss the conceptual underpinnings, experimental evidence and the possible consequences of such a control mechanism. PRELUDE: Whether the detailed examination of parts of the nervous system and their selective perturbation is sufficient to reconstruct how the brain generates behavior, mental disease, music and religion remains an open question. Yet, Sydney Brenner's development of C. elegans as an experimental organism and his faith in the bold reductionist approach that 'the understanding of wild-type behavior comes best after the discovery and analysis of mutations that alter it', has led to discoveries of unexpected roles for neurons in the biology of organisms.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso , Proteostase/fisiologia , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Mamíferos/metabolismo , Modelos Animais , Modelos Biológicos , Rede Nervosa/fisiologiaRESUMO
The coordination between the animal's external environment and internal state requires constant modulation by chemicals known as neuromodulators. Neuromodulators, such as biogenic amines, neuropeptides and cytokines, promote organismal homeostasis. Over the past several decades, Caenorhabditiselegans has grown into a powerful model organism that allows the elucidation of the mechanisms of action of neuromodulators that are conserved across species. In this perspective, we highlight a collection of articles in this issue that describe how neuromodulators optimize C. elegans survival.
Assuntos
Caenorhabditis elegans/fisiologia , Neurotransmissores/fisiologia , Sobrevida/fisiologia , Animais , Aminas Biogênicas/fisiologia , Modelos Animais de Doenças , Homeostase/fisiologia , Modelos Animais , Doenças Neurodegenerativas/fisiopatologia , Neuropeptídeos/fisiologia , Especificidade da EspécieRESUMO
The majority of cilia are formed and maintained by the highly conserved process of intraflagellar transport (IFT). Mutations in IFT genes lead to ciliary structural defects and systemic disorders termed ciliopathies. Here we show that the severely truncated sensory cilia of hypomorphic IFT mutants in C. elegans transiently elongate during a discrete period of adult aging leading to markedly improved sensory behaviors. Age-dependent restoration of cilia morphology occurs in structurally diverse cilia types and requires IFT. We demonstrate that while DAF-16/FOXO is dispensable, the age-dependent suppression of cilia phenotypes in IFT mutants requires cell-autonomous functions of the HSF1 heat shock factor and the Hsp90 chaperone. Our results describe an unexpected role of early aging and protein quality control mechanisms in suppressing ciliary phenotypes of IFT mutants, and suggest possible strategies for targeting subsets of ciliopathies.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Cílios/genética , Fatores de Transcrição Forkhead/genética , Proteínas de Choque Térmico HSP90/genética , Fatores de Transcrição/genética , Envelhecimento/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/biossíntese , Cílios/metabolismo , Ciliopatias/genética , Ciliopatias/terapia , Fatores de Transcrição Forkhead/biossíntese , Proteínas de Choque Térmico HSP90/biossíntese , Humanos , Microtúbulos/genética , Microtúbulos/metabolismo , Chaperonas Moleculares/genética , Mutação , Células Receptoras Sensoriais/metabolismo , Fatores de Transcrição/biossínteseAssuntos
Caenorhabditis elegans/citologia , Neurociências/história , Animais , Linhagem da Célula , Biologia do Desenvolvimento/história , Inglaterra , História do Século XX , Humanos , Modelos Animais , Modelos Neurológicos , Sistema Nervoso/citologia , Neuroglia/fisiologia , Neurônios/fisiologia , Prêmio Nobel , Especificidade da EspécieRESUMO
The consequence of chronic protein misfolding is the basis of many human diseases. To combat the deleterious effects of accumulated protein damage, all cells possess robust quality-control systems, specifically molecular chaperones and clearance machineries, that sense and respond to protein misfolding. However, for many protein conformational diseases, it is unclear why this quality-control system does not efficiently counter protein aggregation. Previous findings that the heat shock response in Caenorhabditis elegans is regulated by thermosensory neurons led us to consider whether neuronal activity could also be responsible for the inadequate response of an organism to chronic protein misfolding. Here we show, in animals expressing polyglutamine expansion proteins and mutant SOD-1(G93A) in intestinal or muscle cells, that the nervous system does indeed control the cellular response to misfolded proteins. Whereas polyglutamine expansion-expressing animals with WT thermosensory neurons readily express protein aggregates, leading to cellular dysfunction without concomitant up-regulation of molecular chaperones, modulation of the nervous system results in chaperone up-regulation that suppresses aggregation and toxicity. The neuronal signal is transmitted through calcium-activated dense core vesicle neurosecretion. Cell-nonautonomous control of chaperone expression by the thermosensory neurons allows C. elegans to respond differently to acute stress such as heat shock, and chronic stress caused by the expression of misfolded proteins, suggesting that neuronal signaling determines the course of cellular proteotoxicity.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Rede Nervosa/metabolismo , Neurônios/metabolismo , Dobramento de Proteína , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Genes Reporter , Fatores de Transcrição de Choque Térmico , Resposta ao Choque Térmico/efeitos dos fármacos , Intestinos/citologia , Mutação/genética , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurossecreção/efeitos dos fármacos , Peptídeos/química , Peptídeos/toxicidade , Estrutura Quaternária de Proteína , Vesículas Secretórias/efeitos dos fármacos , Vesículas Secretórias/metabolismo , Temperatura , Fatores de Transcrição/metabolismo , Expansão das Repetições de Trinucleotídeos , Tropomiosina/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root causes of aging is therefore of critical importance given the rising healthcare burden attributable to age-related diseases. The third annual Midwest Aging Consortium symposium was convened as a showcase of such research performed by investigators from institutions across the Midwestern United States. This report summarizes the work presented during a virtual conference across topics in aging biology, including immune function in the lung-particularly timely given the Corona Virus Immune Disease-2019 pandemic-along with the role of metabolism and nutrient-regulated pathways in cellular function with age, the influence of senescence on stem cell function and inflammation, and our evolving understanding of the mechanisms underlying observation of sex dimorphism in aging-related outcomes. The symposium focused on early-stage and emerging investigators, while including keynote presentations from leaders in the biology of aging field, highlighting the diversity and strength of aging research in the Midwest.
Assuntos
Envelhecimento , Múltiplas Afecções Crônicas , Humanos , Envelhecimento/fisiologia , Inflamação , Pulmão , GerociênciaRESUMO
Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular and multicellular organisms alike. To counteract an imbalance in cellular homeostasis transcriptional programs evolved, called the heat shock response, unfolded protein response, and integrated stress response, that act cell-autonomously in most cells but in multicellular organisms are subjected to cell-nonautonomous regulation. These transcriptional programs downregulate the expression of most genes but increase the expression of heat shock genes, including genes encoding molecular chaperones and proteases, proteins involved in the repair of stress-induced damage to macromolecules and cellular structures. Sixty-one years after the discovery of the heat shock response by Ferruccio Ritossa, many aspects of stress biology are still enigmatic. Recent progress in the understanding of stress responses and molecular chaperones was reported at the 12th International Symposium on Heat Shock Proteins in Biology, Medicine and the Environment in the Old Town Alexandria, VA, USA from 28th to 31st of October 2023.
Assuntos
Proteínas de Choque Térmico , Medicina , Biologia , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico/genética , Chaperonas Moleculares/metabolismoRESUMO
The Second International Symposium on Cellular and Organismal Stress Responses took place virtually on September 8-9, 2022. This meeting was supported by the Cell Stress Society International (CSSI) and organized by Patricija Van Oosten-Hawle and Andrew Truman (University of North Carolina at Charlotte, USA) and Mehdi Mollapour (SUNY Upstate Medical University, USA). The goal of this symposium was to continue the theme from the initial meeting in 2020 by providing a platform for established researchers, new investigators, postdoctoral fellows, and students to present and exchange ideas on various topics on cellular stress and chaperones. We will summarize the highlights of the meeting here and recognize those that received recognition from the CSSI.
Assuntos
Chaperonas Moleculares , Estresse Fisiológico , Humanos , Proteínas de Choque Térmico HSP70 , Chaperonas Moleculares/fisiologia , Estresse Fisiológico/fisiologiaRESUMO
While the average human life span continues to increase, there is little evidence that this is leading to a contemporaneous increase in "healthy years" experienced by our aging population. Consequently, many scientists focus their research on understanding the process of aging and trialing interventions that can promote healthspan. The 2021 Midwest Aging Consortium consensus statement is to develop and further the understanding of aging and age-related disease using the wealth of expertise across universities in the Midwestern United States. This report summarizes the cutting-edge research covered in a virtual symposium held by a consortium of researchers in the Midwestern United States, spanning topics such as senescence biomarkers, serotonin-induced DNA protection, immune system development, multisystem impacts of aging, neural decline following severe infection, the unique transcriptional impact of calorie restriction of different fat depots, the pivotal role of fasting in calorie restriction, the impact of peroxisome dysfunction, and the influence of early life trauma on health. The symposium speakers presented data from studies conducted in a variety of common laboratory animals as well as less-common species, including Caenorhabditis elegans, Drosophila, mice, rhesus macaques, elephants, and humans. The consensus of the symposium speakers is that this consortium highlights the strength of aging research in the Midwestern United States as well as the benefits of a collaborative and diverse approach to geroscience.
Assuntos
Envelhecimento , Pesquisa Biomédica/tendências , Gerociência , Animais , Restrição Calórica , Gerociência/tendências , Humanos , Longevidade , Macaca mulatta , Modelos AnimaisRESUMO
Members of the Cell Stress Society International (CSSI), Patricija van Oosten-Hawle (University of Leeds, UK), Mehdi Mollapour (SUNY Upstate Medical University, USA), Andrew Truman (University of North Carolina at Charlotte, USA) organized a new virtual meeting format which took place on November 5-6, 2020. The goal of this congress was to provide an international platform for scientists to exchange data and ideas among the Cell Stress and Chaperones community during the Covid-19 pandemic. Here we will highlight the summary of the meeting and acknowledge those who were honored by the CSSI.
Assuntos
Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico/genética , Humanos , Chaperonas Moleculares/genética , Proteostase/genética , Proteostase/fisiologiaRESUMO
Serotonin (5-hydroxytryptamine, 5-HT), is a phylogenetically ancient molecule best characterized as a neurotransmitter that modulates multiple aspects of mood and social cognition. The roles that 5-HT plays in normal and abnormal behavior are not fully understood but have been posited to be due to its common function as a 'defense signal'. However, 5-HT levels also systemically impact cell physiology, modulating cell division, migration, apoptosis, mitochondrial biogenesis, cellular metabolism and differentiation. Whether these diverse cellular effects of 5-HT also share a common basis is unclear. C. elegans provides an ideal system to interrogate the systemic effects of 5-HT, since lacking a blood-brain barrier, 5-HT synthesized and released by neurons permeates the organism to modulate neuronal as well as non-neuronal cells throughout the body. Here we used RNA-Seq to characterize the systemic changes in gene expression that occur in C. elegans upon altering 5-HT levels, and compared the transcriptomes to published datasets. We find that an acute increase in 5-HT is accompanied by a global decrease in gene expression levels, upregulation of genes involved in stress pathways, changes that significantly correlate with the published transcriptomes of animals that have activated defense and immune responses, and an increase in levels of phosphorylated eukaryotic initiation factor, eIF2α. In 5-HT deficient animals lacking tryptophan hydroxylase (tph-1(mg280)II) there is a net increase in gene expression, with an overrepresentation of genes related to development and chromatin. Surprisingly, the transcriptomes of animals with acute increases in 5-HT levels, and 5-HT deficiency do not overlap with transcriptomes of mutants with whom they share striking physiological resemblance. These studies are the first to catalog systemic transcriptome changes that occur upon alterations in 5-HT levels. They further show that in C. elegans changes in gene expression upon altering 5-HT levels, and changes in physiology, are not directly correlated.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Serotonina , Transcriptoma , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismoRESUMO
Germ cells are vulnerable to stress. Therefore, how organisms protect their future progeny from damage in a fluctuating environment is a fundamental question in biology. We show that in Caenorhabditis elegans, serotonin released by maternal neurons during stress ensures the viability and stress resilience of future offspring. Serotonin acts through a signal transduction pathway conserved between C. elegans and mammalian cells to enable the transcription factor HSF1 to alter chromatin in soon-to-be fertilized germ cells by recruiting the histone chaperone FACT, displacing histones, and initiating protective gene expression. Without serotonin release by maternal neurons, FACT is not recruited by HSF1 in germ cells, transcription occurs but is delayed, and progeny of stressed C. elegans mothers fail to complete development. These studies uncover a novel mechanism by which stress sensing by neurons is coupled to transcription response times of germ cells to protect future offspring.
Assuntos
Desenvolvimento Embrionário/fisiologia , Células Germinativas/fisiologia , Neurônios/fisiologia , Serotonina/fisiologia , Estresse Fisiológico/fisiologia , Animais , Caenorhabditis elegans/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Proteínas de Ligação a DNA/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição de Choque Térmico/fisiologia , Proteínas de Grupo de Alta Mobilidade/fisiologia , Temperatura Alta , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Fatores de Elongação da Transcrição/fisiologiaRESUMO
Learning, a process by which animals modify their behavior as a result of experience, enables organisms to synthesize information from their surroundings to acquire resources and avoid danger. We showed that a previous encounter with only the odor of pathogenic bacteria prepared Caenorhabditis elegans to survive exposure to the pathogen by increasing the heat shock factor 1 (HSF-1)-dependent expression of genes encoding molecular chaperones. Experience-mediated enhancement of chaperone gene expression required serotonin, which primed HSF-1 to enhance the expression of molecular chaperone genes by promoting its localization to RNA polymerase II-enriched nuclear loci, even before transcription occurred. However, HSF-1-dependent chaperone gene expression was stimulated only if and when animals encountered the pathogen. Thus, learning equips C. elegans to better survive environmental dangers by preemptively and specifically initiating transcriptional mechanisms throughout the whole organism that prepare the animal to respond rapidly to proteotoxic agents. These studies provide one plausible basis for the protective role of environmental enrichment in disease.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Chaperonas Moleculares/metabolismo , Condutos Olfatórios/fisiologia , Fatores de Transcrição/metabolismo , Animais , Animais Geneticamente Modificados , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Escherichia coli/fisiologia , Expressão Gênica , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Chaperonas Moleculares/genética , Pseudomonas aeruginosa/fisiologia , Interferência de RNA , Serotonina/farmacologia , Serratia marcescens/fisiologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genéticaRESUMO
Immunological mediators that originate outside the nervous system can affect neuronal health. However, their roles in neurodegeneration remain largely unknown. Here, we show that the p38MAPK-mediated immune pathway activated in intestinal cells of Caenorhabditis elegans upon mitochondrial dysfunction protects neurons in a cell-non-autonomous fashion. Specifically, mitochondrial complex I dysfunction induced by rotenone activates the p38MAPK/CREB/ATF-7-dependent innate immune response pathway in intestinal cells of C. elegans. Activation of p38MAPK in the gut is neuroprotective. Enhancing the p38MAPK-mediated immune pathway in intestinal cells alone suppresses rotenone-induced dopaminergic neuron loss, while downregulating it in the intestine exacerbates neurodegeneration. The p38MAPK/ATF-7 immune pathway modulates autophagy and requires autophagy and the PTEN-induced putative kinase PINK-1 for conferring neuroprotection. Thus, mitochondrial damage induces the clearance of mitochondria by the immune pathway, protecting the organism from the toxic effects of mitochondrial dysfunction. We propose that mitochondria are subject to constant surveillance by innate immune mechanisms.