RESUMEN
A major challenge for metazoans is to ensure that different tissues, each expressing distinctive proteomes, are nevertheless well protected at an organismal level from proteotoxic stress. We show that expression of endogenous metastable proteins in muscle cells, which rely on chaperones for proper folding, induces a systemic stress response throughout multiple tissues of C. elegans. Suppression of misfolding in muscle cells can be achieved not only by enhanced expression of HSP90 in muscle cells but as effectively by elevated expression of HSP90 in intestine or neuronal cells. This cell-nonautonomous control of HSP90 expression relies upon transcriptional feedback between somatic tissues that is regulated by the FoxA transcription factor PHA-4. This transcellular chaperone signaling response maintains organismal proteostasis when challenged by a local tissue imbalance in folding and provides the basis for organismal stress-sensing surveillance.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Respuesta al Choque Térmico , Transducción de Señal , Transactivadores/metabolismo , Animales , Proteínas de Caenorhabditis elegans/genética , Técnicas de Silenciamiento del Gen , Proteínas HSP90 de Choque Térmico/genética , Mucosa Intestinal/metabolismo , Intestinos/citología , Células Musculares/metabolismo , Miosinas/genética , Miosinas/metabolismo , Pliegue de ProteínaRESUMEN
Amyloid formation by α-synuclein (αSyn) occurs in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Deciphering the residues that regulate αSyn amyloid fibril formation will not only provide mechanistic insight but may also reveal targets to prevent and treat disease. Previous investigations have identified several regions of αSyn to be important in the regulation of amyloid formation, including the non-amyloid-ß component (NAC), P1 region (residues 36 to 42), and residues in the C-terminal domain. Recent studies have also indicated the importance of the N-terminal region of αSyn for both its physiological and pathological roles. Here, the role of residues 2 to 7 in the N-terminal region of αSyn is investigated in terms of their ability to regulate amyloid fibril formation in vitro and in vivo. Deletion of these residues (αSynΔN7) slows the rate of fibril formation in vitro and reduces the capacity of the protein to be recruited by wild-type (αSynWT) fibril seeds, despite cryo-EM showing a fibril structure consistent with those of full-length αSyn. Strikingly, fibril formation of αSynΔN7 is not induced by liposomes, despite the protein binding to liposomes with similar affinity to αSynWT. A Caenorhabditis elegans model also showed that αSynΔN7::YFP forms few puncta and lacks motility and lifespan defects typified by expression of αSynWT::YFP. Together, the results demonstrate the involvement of residues 2 to 7 of αSyn in amyloid formation, revealing a target for the design of amyloid inhibitors that may leave the functional role of the protein in membrane binding unperturbed.
Asunto(s)
Amiloide , Caenorhabditis elegans , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/química , Amiloide/metabolismo , Caenorhabditis elegans/metabolismo , Animales , Humanos , Lípidos/química , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patologíaRESUMEN
Organismal proteostasis is maintained by intercellular signaling processes including cell nonautonomous stress responses such as transcellular chaperone signaling (TCS). When TCS is activated upon tissue-specific knockdown of hsp-90 in the Caenorhabditis elegans intestine, heat-inducible hsp-70 is induced in muscle cells at the permissive temperature resulting in increased heat stress resistance and lifespan extension. However, our understanding of the molecular mechanism and signaling factors mediating transcellular activation of hsp-70 expression from one tissue to another is still in its infancy. Here, we conducted a combinatorial approach using transcriptome RNA-Seq profiling and a forward genetic mutagenesis screen to elucidate how stress signaling from the intestine to the muscle is regulated. We find that the TCS-mediated "gut-to-muscle" induction of hsp-70 expression is suppressed by HSF-1 and instead relies on transcellular-X-cross-tissue (txt) genes. We identify a key role for the PDZ-domain guanylate cyclase txt-1 and the homeobox transcription factor ceh-58 as signaling hubs in the stress receiving muscle cells to initiate hsp-70 expression and facilitate TCS-mediated heat stress resistance and lifespan extension. Our results provide a new view on cell-nonautonomous regulation of "inter-tissue" stress responses in an organism that highlight a key role for the gut. Our data suggest that the HSF-1-mediated heat shock response is switched off upon TCS activation, in favor of an intercellular stress-signaling route to safeguard survival.
Asunto(s)
Proteínas de Caenorhabditis elegans , Animales , Proteínas de Caenorhabditis elegans/metabolismo , Factores de Transcripción/metabolismo , Transducción de Señal , Factores de Transcripción del Choque Térmico/metabolismo , Respuesta al Choque Térmico/genética , Caenorhabditis elegans/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismoRESUMEN
Stress response pathways regulate proteostasis and mitigate macromolecular damage to promote long-term cellular health. Intercellular signaling is an essential layer of systemic proteostasis in an organism and is facilitated via transcellular signaling molecules that orchestrate the activation of stress responses across tissues and organs. Accumulating evidence indicates that components of the immune response act as signaling factors that regulate the cell-non-autonomous proteostasis network. Here, we review emergent advances in our understanding of cell-non-autonomous regulators of proteostasis networks in multicellular settings, from the model organism, Caenorhabditis elegans, to humans. We further discuss how innate immune responses can be players of the organismal proteostasis network and discuss how both are linked in cancer.
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Inmunidad Innata , Proteostasis/inmunología , Estrés Fisiológico/inmunología , Animales , Citocinas/metabolismo , Regulación de la Expresión Génica , Humanos , Inmunidad Innata/inmunología , Neoplasias/metabolismo , Pliegue de Proteína , ARN Largo no Codificante , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Transcitosis , Vasculitis Leucocitoclástica Cutánea/metabolismoRESUMEN
Protein quality control is essential in all organisms and regulated by the proteostasis network (PN) and cell stress response pathways that maintain a functional proteome to promote cellular health. In this review, we describe how metazoans employ multiple modes of cell-nonautonomous signaling across tissues to integrate and transmit the heat-shock response (HSR) for balanced expression of molecular chaperones. The HSR and other cell stress responses such as the unfolded protein response (UPR) can function autonomously in single-cell eukaryotes and tissue culture cells; however, within the context of a multicellular animal, the PN is regulated by cell-nonautonomous signaling through specific sensory neurons and by the process of transcellular chaperone signaling. These newly identified forms of stress signaling control the PN between neurons and nonneuronal somatic tissues to achieve balanced tissue expression of chaperones in response to environmental stress and to ensure that metastable aggregation-prone proteins expressed within any single tissue do not generate local proteotoxic risk. Transcellular chaperone signaling leads to the compensatory expression of chaperones in other somatic tissues of the animal, perhaps preventing the spread of proteotoxic damage. Thus, communication between subcellular compartments and across different cells and tissues maintains proteostasis when challenged by acute stress and upon chronic expression of metastable proteins. We propose that transcellular chaperone signaling provides a critical control step for the PN to maintain cellular and organismal health span.
Asunto(s)
Regulación de la Expresión Génica , Chaperonas Moleculares/metabolismo , Proteoma , Transducción de Señal , Animales , Caenorhabditis elegans , Respuesta al Choque Térmico , Estrés FisiológicoRESUMEN
Aggregation of ß2 microglobulin (ß2m) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type protein and its truncated variant, ΔN6 ß2m, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the ß2m variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of ß2 microglobulin have been widely studied in vitro and in vivo, we lack a comparable understanding of the molecular mechanisms underlying toxicity in a cellular and organismal environment. Here, we established transgenic C. elegans lines expressing wild-type (WT) human ß2m, or the two highly amyloidogenic naturally occurring variants, D76N ß2m and ΔN6 ß2m, in the C. elegans bodywall muscle. Nematodes expressing the D76N ß2m and ΔN6 ß2m variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both ß2m variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of ß2m reduces the capacity of C. elegans to cope with heat and endoplasmic reticulum (ER) stress, correlating with a deficiency to upregulate BiP/hsp-4 transcripts in response to ER stress in young adult animals. Interestingly, protein secretion in all ß2m variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal ß2m toxicity and a disrupted ER secretory metabolism.
Asunto(s)
Caenorhabditis elegans/crecimiento & desarrollo , Estrés del Retículo Endoplásmico , Longevidad , Mutación , Agregado de Proteínas , Respuesta de Proteína Desplegada , Microglobulina beta-2/toxicidad , Animales , Caenorhabditis elegans/genética , Respuesta al Choque Térmico , Humanos , Microglobulina beta-2/genéticaRESUMEN
Eukaryotic organisms have evolved complex and robust cellular stress response pathways to ensure maintenance of proteostasis and survival during fluctuating environmental conditions. Highly conserved stress response pathways can be triggered and coordinated at the cell-autonomous and cell-nonautonomous level by proteostasis transcription factors, including HSF1, SKN-1/NRF2, HIF1, and DAF-16/FOXO that combat proteotoxic stress caused by environmental challenges. While these transcription factors are often associated with a specific stress condition, they also direct "noncanonical" transcriptional programs that serve to integrate a multitude of physiological responses required for development, metabolism, and defense responses to pathogen infections. In this review, we outline the established function of these key proteostasis transcription factors at the cell-autonomous and cell-nonautonomous level and discuss a newly emerging stress responsive transcription factor, PQM-1, within the proteostasis network. We look beyond the canonical stress response roles of proteostasis transcription factors and highlight their function in integrating different physiological stimuli to maintain cytosolic organismal proteostasis.
Asunto(s)
Salud/normas , Metabolismo/fisiología , Proteostasis/fisiología , Estrés Fisiológico/fisiología , Factores de Transcripción/metabolismo , HumanosRESUMEN
The formation of amyloid fibres is a hallmark of amyloid disorders. Nevertheless, the lack of correlation between fibre load and disease as observed, for example, in Alzheimer's disease, means that fibres are considered secondary contributors to the onset of cellular dysfunction. Instead, soluble intermediates of amyloid assembly are often described as the agents of toxicity. Here, we discuss recent experimental discoveries which suggest that amyloid fibres should be considered as disease-relevant species that can mediate a range of pathological processes. These include disruption of biological membranes, secondary nucleation, amyloid aggregate transmission, and the disruption of protein homeostasis (proteostasis). Thus, a greater understanding of amyloid fibre biology could enhance prospects of developing therapeutic interventions against this devastating class of protein-misfolding disorders.
Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Deficiencias en la Proteostasis/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Amiloide/química , Animales , Humanos , Agregación Patológica de Proteínas , Deficiencias en la Proteostasis/tratamiento farmacológicoRESUMEN
Managing the emergence and spread of crop pests and pathogens is essential for global food security. Understanding how organisms have adapted to their native climate is key to predicting the impact of climate change. The potato cyst nematodes Globodera pallida and G. rostochiensis are economically important plant pathogens that cause yield losses of up to 50% in potato. The two species have different thermal optima that may relate to differences in the altitude of their regions of origin in the Andes. Here, we demonstrate that juveniles of G. pallida are less able to recover from heat stress than those of G. rostochiensis. Genome-wide analysis revealed that while both Globodera species respond to heat stress by induction of various protective heat-inducible genes, G. pallida experiences heat stress at lower temperatures. We use C. elegans as a model to demonstrate the dependence of the heat stress response on expression of Heat Shock Factor-1 (HSF-1). Moreover, we show that hsp-110 is induced by heat stress in G. rostochiensis, but not in the less thermotolerant G. pallida. Sequence analysis revealed that this gene and its promoter was duplicated in G. rostochiensis and acquired thermoregulatory properties. We show that hsp-110 is required for recovery from acute thermal stress in both C. elegans and in G. rostochiensis. Our findings point towards an underlying molecular mechanism that allows the differential expansion of one species relative to another closely related species under current climate change scenarios. Similar mechanisms may be true of other invertebrate species with pest status.
Asunto(s)
Cambio Climático , Duplicación de Gen , Proteínas del Choque Térmico HSP110/genética , Respuesta al Choque Térmico , Rabdítidos/genética , Animales , Femenino , Proteínas del Choque Térmico HSP110/metabolismo , Calor , Rabdítidos/metabolismo , Especificidad de la EspecieRESUMEN
The ability of each cell within a metazoan to adapt to and survive environmental and physiological stress requires cellular stress-response mechanisms, such as the heat shock response (HSR). Recent advances reveal that cellular proteostasis and stress responses in metazoans are regulated by multiple layers of intercellular communication. This ensures that an imbalance of proteostasis that occurs within any single tissue 'at risk' is protected by a compensatory activation of a stress response in adjacent tissues that confers a community protective response. While each cell expresses the machinery for heat shock (HS) gene expression, the HSR is regulated cell non-autonomously in multicellular organisms, by neuronal signaling to the somatic tissues, and by transcellular chaperone signaling between somatic tissues and from somatic tissues to neurons. These cell non-autonomous processes ensure that the organismal HSR is orchestrated across multiple tissues and that transmission of stress signals between tissues can also override the neuronal control to reset cell- and tissue-specific proteostasis. Here, we discuss emerging concepts and insights into the complex cell non-autonomous mechanisms that control stress responses in metazoans and highlight the importance of intercellular communication for proteostasis maintenance in multicellular organisms.
Asunto(s)
Caenorhabditis elegans/fisiología , Comunicación Celular/fisiología , Respuesta al Choque Térmico/fisiología , Estrés Fisiológico/fisiología , Respuesta de Proteína Desplegada/fisiología , Envejecimiento , Animales , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Retículo Endoplásmico/fisiología , Proteínas de Choque Térmico/metabolismo , Pliegue de Proteína , Células Receptoras Sensoriales/metabolismo , Transducción de Señal/fisiología , Factores de Transcripción/metabolismoRESUMEN
Heat shock can be a lethal stressor. Previously, we described a CUL-6/cullin-ring ubiquitin ligase complex in the nematode Caenorhabditis elegans that is induced by intracellular intestinal infection and proteotoxic stress and that promotes improved survival upon heat shock (thermotolerance). Here, we show that CUL-6 promotes thermotolerance by targeting the heat shock protein HSP-90 for degradation. We show that CUL-6-mediated lowering of HSP-90 protein levels, specifically in the intestine, improves thermotolerance. Furthermore, we show that lysosomal function is required for CUL-6-mediated promotion of thermotolerance and that CUL-6 directs HSP-90 to lysosome-related organelles upon heat shock. Altogether, these results indicate that a CUL-6 ubiquitin ligase promotes organismal survival upon heat shock by promoting HSP-90 degradation in intestinal lysosomes. Thus, HSP-90, a protein commonly associated with protection against heat shock and promoting degradation of other proteins, is itself degraded to protect against heat shock.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas HSP90 de Choque Térmico , Lisosomas , Termotolerancia , Animales , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas Cullin/metabolismo , Respuesta al Choque Térmico , Proteínas HSP90 de Choque Térmico/metabolismo , Intestinos , Lisosomas/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
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.
Asunto(s)
Proteínas de Choque Térmico , Medicina , Biología , Proteínas de Choque Térmico/metabolismo , Respuesta al Choque Térmico/genética , Chaperonas Moleculares/metabolismoRESUMEN
Aging results in a decline of cellular proteostasis capacity which culminates in the accumulation of phototoxic material, causing the onset of age-related maladies and ultimately cell death. Mechanisms that regulate proteostasis such as cellular stress response pathways sense disturbances in the proteome. They are activated to increase the expression of protein quality control components that counteract cellular damage. Utilizing invertebrate model organisms such as Caenorhabditis elegans, it has become increasingly evident that the regulation of proteostasis and the activation of cellular stress responses is not a cell autonomous process. In animals, stress responses are orchestrated by signals coming from other tissues, including the nervous system, the intestine and the germline that have a profound impact on determining the aging process. Genetic pathways discovered in C. elegans that facilitate cell nonautonomous regulation of stress responses are providing an exciting feeding ground for new interventions. In this review I will discuss cell nonautonomous proteostasis mechanisms and their impact on aging as well as ongoing research and clinical trials that can increase organismal proteostasis to lengthen health- and lifespan.
RESUMEN
Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation to environmental stresses. Emerging research shows that Hsp90 function in an organism goes well beyond intracellular proteostasis. In metazoans, Hsp90, as an environmentally responsive chaperone, is involved in inter-tissue stress signaling responses that coordinate and safeguard cell nonautonomous proteostasis and organismal health. In this way, Hsp90 has the capacity to influence evolution and aging, and effect behavioral responses to facilitate tissue-defense systems that ensure organismal survival. In this review, I summarize the literature on the organismal roles of Hsp90 uncovered in multicellular organisms, from plants to invertebrates and mammals.
Asunto(s)
Proteínas HSP90 de Choque Térmico , Chaperonas Moleculares , Humanos , Animales , Proteínas HSP90 de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Transducción de Señal , Proteostasis , Estrés Fisiológico , Mamíferos/metabolismoRESUMEN
Serine/threonine protein phosphatases play a significant role in the survival and propagation of multiple cancers. In this issue of Cell Chemical Biology, Ahanin et al.1 demonstrate that protein phosphatase 5 (PP5) dephosphorylates and inactivates the cell death effector protein FADD independently of Hsp90, and they identify a selective PP5 inhibitor as a new therapeutic strategy for renal cancer.
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Neoplasias , Fosfoproteínas Fosfatasas , Proteínas Nucleares/metabolismo , Muerte Celular , Neoplasias/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Chaperonas Moleculares , Estrés Fisiológico , Humanos , Proteínas HSP70 de Choque Térmico , Chaperonas Moleculares/fisiología , Estrés Fisiológico/fisiologíaRESUMEN
In multicellular organisms such as Caenorhabditis elegans, cellular stress stimuli and responses are communicated between tissues to promote organismal health- and lifespan. The nervous system is the predominant regulator of cell nonautonomous proteostasis that orchestrates systemic stress responses to integrate both internal and external stimuli. This review highlights the role of the intestine in mediating cell nonautonomous stress responses and explores recent findings that suggest a central role for the intestine to regulate organismal proteostasis. As a tissue that receives and further transduces signals from the nervous system in response to dietary restriction, heat- and oxidative stress, and hypoxia, we explore evidence suggesting the intestine is a key regulatory organ itself. From the perspective of naturally occurring stressors such as dietary restriction and pathogen infection we highlight how the intestine can function as a key regulator of organismal proteostasis by integrating insulin/IGF-like signaling, miRNA-, neuropeptide- and metabolic signaling to alter distal tissue functions in promoting survival, health- and lifespan.