Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.691
Filtrar
Mais filtros

Intervalo de ano de publicação
1.
Cell ; 187(16): 4289-4304.e26, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-38942015

RESUMO

Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-ß response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.


Assuntos
Matriz Extracelular , Homeostase , Mitocôndrias , Resposta a Proteínas não Dobradas , Matriz Extracelular/metabolismo , Animais , Mitocôndrias/metabolismo , Humanos , Fator de Crescimento Transformador beta/metabolismo , Dinâmica Mitocondrial , Camundongos , Transdução de Sinais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/imunologia
2.
Cell ; 187(17): 4605-4620.e17, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-38959891

RESUMO

The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the Wnt ligand EGL-20, which activate the mitochondrial unfolded protein response (UPRMT) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-periphery UPRMT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, Wnt and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPRMT activation. We also find that the germline tissue itself is essential for UPRMT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Células Germinativas , Mitocôndrias , Transdução de Sinais , Resposta a Proteínas não Dobradas , Animais , Caenorhabditis elegans/metabolismo , Mitocôndrias/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Células Germinativas/metabolismo , Neurônios/metabolismo , Serotonina/metabolismo , Proteínas Wnt/metabolismo
3.
Annu Rev Immunol ; 33: 107-38, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25493331

RESUMO

Immune responses occur in the midst of a variety of cellular stresses that can severely perturb endoplasmic reticulum (ER) function. The unfolded protein response is a three-pronged signaling axis dedicated to preserving ER homeostasis. In this review, we highlight many important and emerging functional roles for ER stress in immunity, focusing on how the bidirectional cross talk between immunological processes and basic cell biology leads to pleiotropic signaling outcomes and enhanced sensitivity to inflammatory stimuli. We also discuss how dysregulated ER stress responses can provoke many diseases, including autoimmunity, firmly positioning the unfolded protein response as a major therapeutic target in human disease.


Assuntos
Estresse do Retículo Endoplasmático/imunologia , Imunidade , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Autoimunidade , Diferenciação Celular/imunologia , Retículo Endoplasmático/metabolismo , Humanos , Fenômenos do Sistema Imunitário , Infecções/etiologia , Infecções/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Ligação Proteica , Transdução de Sinais , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas
4.
Annu Rev Biochem ; 89: 529-555, 2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32097570

RESUMO

Protein folding in the cell is mediated by an extensive network of >1,000 chaperones, quality control factors, and trafficking mechanisms collectively termed the proteostasis network. While the components and organization of this network are generally well established, our understanding of how protein-folding problems are identified, how the network components integrate to successfully address challenges, and what types of biophysical issues each proteostasis network component is capable of addressing remains immature. We describe a chemical biology-informed framework for studying cellular proteostasis that relies on selection of interesting protein-folding problems and precise researcher control of proteostasis network composition and activities. By combining these methods with multifaceted strategies to monitor protein folding, degradation, trafficking, and aggregation in cells, researchers continue to rapidly generate new insights into cellular proteostasis.


Assuntos
Chaperonas Moleculares/genética , Técnicas de Sonda Molecular , Proteoma/genética , Deficiências na Proteostase/genética , Proteostase/genética , Animais , Sistemas CRISPR-Cas , Regulação da Expressão Gênica , Meia-Vida , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Chaperonas Moleculares/metabolismo , Agregados Proteicos , Engenharia de Proteínas/métodos , Dobramento de Proteína/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteoma/química , Proteoma/metabolismo , Proteostase/efeitos dos fármacos , Deficiências na Proteostase/metabolismo , Deficiências na Proteostase/patologia , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos
5.
Cell ; 180(6): 1160-1177.e20, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32160526

RESUMO

Selective autophagy of organelles is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few autophagosomal receptors and remodelers. By using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence human ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which is opposite of general autophagy and is independent of AMPK. Second, ER-localized UFMylation is required for ER-phagy to repress the unfolded protein response via IRE1α. The UFL1 ligase is brought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentially targets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network.


Assuntos
Autofagia/fisiologia , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Autofagia/genética , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Estudo de Associação Genômica Ampla/métodos , Células HCT116 , Células HEK293 , Células HeLa , Homeostase , Humanos , Proteínas de Membrana/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/metabolismo , Proteínas Ribossômicas/metabolismo , Resposta a Proteínas não Dobradas/fisiologia
6.
Nat Immunol ; 23(3): 431-445, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35228694

RESUMO

Chronic inflammation triggers compensatory immunosuppression to stop inflammation and minimize tissue damage. Studies have demonstrated that endoplasmic reticulum (ER) stress augments the suppressive phenotypes of immune cells; however, the molecular mechanisms underpinning this process and how it links to the metabolic reprogramming of immunosuppressive macrophages remain elusive. In the present study, we report that the helper T cell 2 cytokine interleukin-4 and the tumor microenvironment increase the activity of a protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. PERK activation mediated the upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis resulted in enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification. Inhibition of PERK suppressed macrophage immunosuppressive activity and could enhance the efficacy of immune checkpoint programmed cell death protein 1 inhibition in melanoma. Our findings delineate a previously undescribed connection between PERK signaling and PSAT1-mediated serine metabolism critical for promoting immunosuppressive function in M2 macrophages.


Assuntos
Estresse do Retículo Endoplasmático , eIF-2 Quinase , Estresse do Retículo Endoplasmático/genética , Macrófagos/metabolismo , Transdução de Sinais , Resposta a Proteínas não Dobradas , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
7.
Cell ; 177(5): 1088-1090, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100264

RESUMO

Mogilenko et al. dissect mechanisms by which fatty acids lead to a state of heightened innate immunity and inflammation. They reveal a metabolic adaptation to elevated fatty acids that involves a shift in the balance between glycolysis and oxidative phosphorylation and activation of the unfolded protein response, linking the high-fat Western diet to systemic inflammatory disease.


Assuntos
Sinais (Psicologia) , Ácidos Graxos , Sistema Imunitário , Imunidade Inata , Resposta a Proteínas não Dobradas
8.
Cell ; 179(6): 1246-1248, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31778650

RESUMO

Cells are protected from endoplasmic reticulum stress through the unfolded protein response (UPR). In this issue of Cell, Schinzel, Higuchi-Sanabria, Shalem et al., identify a mechanism that helps cells cope with ER stress but is independent of canonical UPR activation, instead involving the extracellular matrix hyaluronidase, TMEM2, as a signaling mediator.


Assuntos
Hialuronoglucosaminidase , Longevidade , Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Homeostase , Resposta a Proteínas não Dobradas
9.
Cell ; 177(5): 1201-1216.e19, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31031005

RESUMO

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.


Assuntos
Microambiente Celular/imunologia , Células Dendríticas/imunologia , Imunidade Inata , Mitocôndrias/imunologia , Espécies Reativas de Oxigênio/imunologia , Resposta a Proteínas não Dobradas/imunologia , Animais , Microambiente Celular/genética , Ciclo do Ácido Cítrico/genética , Ciclo do Ácido Cítrico/imunologia , Células Dendríticas/patologia , Hexoquinase/genética , Hexoquinase/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Resposta a Proteínas não Dobradas/genética , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/imunologia
10.
Cell ; 179(6): 1306-1318.e18, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31761535

RESUMO

Cells have evolved complex mechanisms to maintain protein homeostasis, such as the UPRER, which are strongly associated with several diseases and the aging process. We performed a whole-genome CRISPR-based knockout (KO) screen to identify genes important for cells to survive ER-based protein misfolding stress. We identified the cell-surface hyaluronidase (HAase), Transmembrane Protein 2 (TMEM2), as a potent modulator of ER stress resistance. The breakdown of the glycosaminoglycan, hyaluronan (HA), by TMEM2 within the extracellular matrix (ECM) altered ER stress resistance independent of canonical UPRER pathways but dependent upon the cell-surface receptor, CD44, a putative HA receptor, and the MAPK cell-signaling components, ERK and p38. Last, and most surprisingly, ectopic expression of human TMEM2 in C. elegans protected animals from ER stress and increased both longevity and pathogen resistance independent of canonical UPRER activation but dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.


Assuntos
Caenorhabditis elegans/fisiologia , Retículo Endoplasmático/metabolismo , Hialuronoglucosaminidase/metabolismo , Longevidade/fisiologia , Proteínas de Membrana/metabolismo , Resposta a Proteínas não Dobradas , Animais , Caenorhabditis elegans/imunologia , Linhagem Celular , Proliferação de Células , Resistência à Doença , Estresse do Retículo Endoplasmático , Fibroblastos/metabolismo , Humanos , Imunidade Inata , Modelos Biológicos , Peso Molecular , Transdução de Sinais
11.
Cell ; 178(3): 521-535.e23, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348885

RESUMO

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.


Assuntos
Benzamidas/metabolismo , Compostos Bicíclicos com Pontes/farmacologia , Heptanos/farmacologia , Lisossomos/efeitos dos fármacos , Proteínas de Transporte Vesicular/metabolismo , Fator 6 Ativador da Transcrição/metabolismo , Animais , Benzamidas/química , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/uso terapêutico , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Mutação da Fase de Leitura , Heptanos/uso terapêutico , Humanos , Receptores de Imidazolinas/antagonistas & inibidores , Receptores de Imidazolinas/genética , Receptores de Imidazolinas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Rim/citologia , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mucina-1/química , Mucina-1/genética , Mucina-1/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Proteínas de Transporte Vesicular/química
12.
Annu Rev Cell Dev Biol ; 36: 165-189, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33021824

RESUMO

As the world's population ages, neurodegenerative disorders are poised to become the commonest cause of death. Despite this, they remain essentially untreatable. Characterized pathologically both by the aggregation of disease-specific misfolded proteins and by changes in cellular stress responses, to date, therapeutic approaches have focused almost exclusively on reducing misfolded protein load-notably amyloid beta (Aß) in Alzheimer's disease. The repeated failure of clinical trials has led to despondency over the possibility that these disorders will ever be treated. We argue that this is in fact a time for optimism: Targeting various generic stress responses is emerging as an increasingly promising means of modifying disease progression across these disorders. New treatments are approaching clinical trials, while novel means of targeting aggregates could eventually act preventively in early disease.


Assuntos
Doenças Neurodegenerativas/terapia , Agregados Proteicos , Estresse Fisiológico , Animais , Autofagossomos/metabolismo , Humanos , Lisossomos/metabolismo , Resposta a Proteínas não Dobradas
13.
Cell ; 174(4): 870-883.e17, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30057120

RESUMO

The mitochondrial unfolded protein response (UPRmt) can be triggered in a cell-non-autonomous fashion across multiple tissues in response to mitochondrial dysfunction. The ability to communicate information about the presence of mitochondrial stress enables a global response that can ultimately better protect an organism from local mitochondrial challenges. We find that animals use retromer-dependent Wnt signaling to propagate mitochondrial stress signals from the nervous system to peripheral tissues. Specifically, the polyQ40-triggered activation of mitochondrial stress or reduction of cco-1 (complex IV subunit) in neurons of C. elegans results in the Wnt-dependent induction of cell-non-autonomous UPRmt in peripheral cells. Loss-of-function mutations of retromer complex components that are responsible for recycling the Wnt secretion-factor/MIG-14 prevent Wnt secretion and thereby suppress cell-non-autonomous UPRmt. Neuronal expression of the Wnt ligand/EGL-20 is sufficient to induce cell-non-autonomous UPRmt in a retromer complex-, Wnt signaling-, and serotonin-dependent manner, clearly implicating Wnt signaling as a strong candidate for the "mitokine" signal.


Assuntos
Animais Geneticamente Modificados/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Mitocôndrias/metabolismo , Poliubiquitina/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Proteínas Wnt/metabolismo , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/crescimento & desenvolvimento , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Mitocôndrias/genética , Neurônios/citologia , Neurônios/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas Wnt/genética
14.
Cell ; 173(1): 62-73.e9, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29526462

RESUMO

Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to ß cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity. By testing variants of the human homolog, ZMPSTE24, with varying activity levels, the rescue of IAPP toxicity proved to be directly proportional to the declogging efficiency. Clinically relevant ZMPSTE24 variants identified in the largest database of exomes sequences derived from T2D patients were characterized using the yeast model, revealing 14 partial loss-of-function variants, which were enriched among diabetes patients over 2-fold. Thus, clogging of the translocon by IAPP oligomers may contribute to ß cell failure.


Assuntos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Proteínas de Membrana/metabolismo , Metaloendopeptidases/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/toxicidade , Proteínas de Membrana/química , Proteínas de Membrana/genética , Metaloendopeptidases/química , Metaloendopeptidases/genética , Modelos Biológicos , Mutagênese , Agregados Proteicos/fisiologia , Estrutura Terciária de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos
15.
Annu Rev Cell Dev Biol ; 35: 477-500, 2019 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-31340124

RESUMO

Autophagy is the major cellular pathway to degrade dysfunctional organelles and protein aggregates. Autophagy is particularly important in neurons, which are terminally differentiated cells that must last the lifetime of the organism. There are both constitutive and stress-induced pathways for autophagy in neurons, which catalyze the turnover of aged or damaged mitochondria, endoplasmic reticulum, other cellular organelles, and aggregated proteins. These pathways are required in neurodevelopment as well as in the maintenance of neuronal homeostasis. Here we review the core components of the pathway for autophagosome biogenesis, as well as the cell biology of bulk and selective autophagy in neurons. Finally, we discuss the role of autophagy in neuronal development, homeostasis, and aging and the links between deficits in autophagy and neurodegeneration.


Assuntos
Autofagia/genética , Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Animais , Autofagossomos/metabolismo , Autofagia/fisiologia , Axônios/metabolismo , Dendritos/metabolismo , Retículo Endoplasmático/fisiologia , Homeostase/genética , Homeostase/fisiologia , Humanos , Memória/fisiologia , Mitocôndrias/enzimologia , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurônios/citologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia , Ubiquitinação/genética , Ubiquitinação/fisiologia , Resposta a Proteínas não Dobradas/genética , Resposta a Proteínas não Dobradas/fisiologia
16.
Nat Rev Mol Cell Biol ; 21(8): 421-438, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32457508

RESUMO

Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the unfolded protein response (UPR), a signal transduction pathway that senses the fidelity of protein folding in the ER lumen. The UPR transmits information about protein folding status to the nucleus and cytosol to adjust the protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Resposta a Proteínas não Dobradas/genética , Resposta a Proteínas não Dobradas/fisiologia , Animais , Apoptose/fisiologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/fisiologia , Humanos , Neoplasias/metabolismo , Dobramento de Proteína , Proteínas/metabolismo , Transdução de Sinais
17.
Cell ; 168(4): 692-706, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28187289

RESUMO

Malignant cells utilize diverse strategies that enable them to thrive under adverse conditions while simultaneously inhibiting the development of anti-tumor immune responses. Hostile microenvironmental conditions within tumor masses, such as nutrient deprivation, oxygen limitation, high metabolic demand, and oxidative stress, disturb the protein-folding capacity of the endoplasmic reticulum (ER), thereby provoking a cellular state of "ER stress." Sustained activation of ER stress sensors endows malignant cells with greater tumorigenic, metastatic, and drug-resistant capacity. Additionally, recent studies have uncovered that ER stress responses further impede the development of protective anti-cancer immunity by manipulating the function of myeloid cells in the tumor microenvironment. Here, we discuss the tumorigenic and immunoregulatory effects of ER stress in cancer, and we explore the concept of targeting ER stress responses to enhance the efficacy of standard chemotherapies and evolving cancer immunotherapies in the clinic.


Assuntos
Estresse do Retículo Endoplasmático , Neoplasias/imunologia , Neoplasias/patologia , Animais , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Evasão Tumoral , Microambiente Tumoral , Resposta a Proteínas não Dobradas
18.
Cell ; 171(7): 1625-1637.e13, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29198525

RESUMO

When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response (UPR) increases ER-protein-folding capacity to restore protein-folding homeostasis. Unfolded proteins activate UPR signaling across the ER membrane to the nucleus by promoting oligomerization of IRE1, a conserved transmembrane ER stress receptor. However, the coupling of ER stress to IRE1 oligomerization and activation has remained obscure. Here, we report that the ER luminal co-chaperone ERdj4/DNAJB9 is a selective IRE1 repressor that promotes a complex between the luminal Hsp70 BiP and the luminal stress-sensing domain of IRE1α (IRE1LD). In vitro, ERdj4 is required for complex formation between BiP and IRE1LD. ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. These observations establish BiP and its J domain co-chaperones as key regulators of the UPR.


Assuntos
Endorribonucleases/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Resposta a Proteínas não Dobradas , Animais , Cricetinae , Retículo Endoplasmático/metabolismo , Chaperona BiP do Retículo Endoplasmático , Humanos , Dobramento de Proteína
19.
Cell ; 169(7): 1249-1262.e13, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28622510

RESUMO

Homeostasis of the gut microbiota critically influences host health and aging. Developing genetically engineered probiotics holds great promise as a new therapeutic paradigm to promote healthy aging. Here, through screening 3,983 Escherichia coli mutants, we discovered that 29 bacterial genes, when deleted, increase longevity in the host Caenorhabditis elegans. A dozen of these bacterial mutants also protect the host from age-related progression of tumor growth and amyloid-beta accumulation. Mechanistically, we discovered that five bacterial mutants promote longevity through increased secretion of the polysaccharide colanic acid (CA), which regulates mitochondrial dynamics and unfolded protein response (UPRmt) in the host. Purified CA polymers are sufficient to promote longevity via ATFS-1, the host UPRmt-responsive transcription factor. Furthermore, the mitochondrial changes and longevity effects induced by CA are conserved across different species. Together, our results identified molecular targets for developing pro-longevity microbes and a bacterial metabolite acting on host mitochondria to promote longevity.


Assuntos
Caenorhabditis elegans/microbiologia , Escherichia coli/genética , Longevidade , Envelhecimento/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Carga Bacteriana , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Escherichia coli/metabolismo , Deleção de Genes , Estudo de Associação Genômica Ampla , Dinâmica Mitocondrial , Modelos Animais , Polissacarídeos/metabolismo , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas
20.
Annu Rev Biochem ; 85: 1-4, 2016 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-27050288

RESUMO

Aging and longevity are controlled by a multiplicity of molecular and cellular signaling events that interface with environmental factors to maintain cellular homeostasis. Modulation of these pathways to extend life span, including insulin-like signaling and the response to dietary restriction, identified the cellular machineries and networks of protein homeostasis (proteostasis) and stress resistance pathways as critical players in the aging process. A decline of proteostasis capacity during aging leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to a range of chronic diseases. This volume of the Annual Review of Biochemistry contains a set of two reviews addressing our current understanding of the molecular mechanisms underlying aging in model organisms and humans.


Assuntos
Envelhecimento/genética , Caenorhabditis elegans/genética , Fator de Iniciação 2 em Eucariotos/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Serina-Treonina Quinases/genética , Resposta a Proteínas não Dobradas , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Restrição Calórica , Fator de Iniciação 2 em Eucariotos/metabolismo , Homeostase/genética , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Estabilidade Proteica , Proteólise , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo , Deficiências na Proteostase/patologia , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA