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Cellular & Molecular Immunology Mar 2016Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β. Among various... (Review)
Review
Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β. Among various inflammasome complexes, the NLRP3 inflammasome is best characterized and has been linked with various human autoinflammatory and autoimmune diseases. Thus, the NLRP3 inflammasome may be a promising target for anti-inflammatory therapies. In this review, we summarize the current understanding of the mechanisms by which the NLRP3 inflammasome is activated in the cytosol. We also describe the binding partners of NLRP3 inflammasome complexes activating or inhibiting the inflammasome assembly. Our knowledge of the mechanisms regulating NLRP3 inflammasome signaling and how these influence inflammatory responses offers further insight into potential therapeutic strategies to treat inflammatory diseases associated with dysregulation of the NLRP3 inflammasome.
Topics: Animals; Autoimmune Diseases; Cytosol; Humans; Inflammasomes; Inflammation; Interleukin-1beta; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction
PubMed: 26549800
DOI: 10.1038/cmi.2015.95 -
Nature Cell Biology Sep 2017Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory...
Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP.
Topics: Animals; Cell Proliferation; Cells, Cultured; Cellular Senescence; Chromatin; Cytosol; Enzyme Activation; Female; Genotype; Immunity, Innate; Male; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Nucleotidyltransferases; Oxidative Stress; Paracrine Communication; Phenotype; RNA Interference; Signal Transduction; Time Factors; Transfection
PubMed: 28759028
DOI: 10.1038/ncb3586 -
Nature Mar 2017Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction. Although many...
Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction. Although many neurodegenerative-disease-associated proteins can be found in mitochondria, it remains unclear how mitochondrial dysfunction and protein aggregation could be related. In dividing yeast cells, protein aggregates that form under stress or during ageing are preferentially retained by the mother cell, in part through tethering to mitochondria, while the disaggregase Hsp104 helps to dissociate aggregates and thereby enables refolding or degradation of misfolded proteins. Here we show that, in yeast, cytosolic proteins prone to aggregation are imported into mitochondria for degradation. Protein aggregates that form under heat shock contain both cytosolic and mitochondrial proteins and interact with the mitochondrial import complex. Many aggregation-prone proteins enter the mitochondrial intermembrane space and matrix after heat shock, and some do so even without stress. Timely dissolution of cytosolic aggregates requires the mitochondrial import machinery and proteases. Blocking mitochondrial import but not proteasome activity causes a marked delay in the degradation of aggregated proteins. Defects in cytosolic Hsp70s leads to enhanced entry of misfolded proteins into mitochondria and elevated mitochondrial stress. We term this mitochondria-mediated proteostasis mechanism MAGIC (mitochondria as guardian in cytosol) and provide evidence that it may exist in human cells.
Topics: Cell Line; Cytosol; HSP70 Heat-Shock Proteins; Heat-Shock Response; Homeostasis; Humans; Mitochondria; Mitochondrial Proteins; Peptide Hydrolases; Proteasome Endopeptidase Complex; Protein Aggregates; Protein Folding; Protein Refolding; Protein Stability; Protein Transport; Proteins; Proteolysis; Saccharomyces cerevisiae
PubMed: 28241148
DOI: 10.1038/nature21695 -
Developmental Cell Jan 2021Cytoplasm is a gel-like crowded environment composed of various macromolecules, organelles, cytoskeletal networks, and cytosol. The structure of the cytoplasm is highly... (Review)
Review
Cytoplasm is a gel-like crowded environment composed of various macromolecules, organelles, cytoskeletal networks, and cytosol. The structure of the cytoplasm is highly organized and heterogeneous due to the crowding of its constituents and their effective compartmentalization. In such an environment, the diffusive dynamics of the molecules are restricted, an effect that is further amplified by clustering and anchoring of molecules. Despite the crowded nature of the cytoplasm at the microscopic scale, large-scale reorganization of the cytoplasm is essential for important cellular functions, such as cell division and polarization. How such mesoscale reorganization of the cytoplasm is achieved, especially for large cells such as oocytes or syncytial tissues that can span hundreds of micrometers in size, is only beginning to be understood. In this review, we will discuss recent advances in elucidating the molecular, cellular, and biophysical mechanisms by which the cytoskeleton drives cytoplasmic reorganization across different scales, structures, and species.
Topics: Animals; Cytoplasm; Cytoskeleton; Cytosol; Humans; Mechanotransduction, Cellular; Multiprotein Complexes; Organelles
PubMed: 33321104
DOI: 10.1016/j.devcel.2020.12.002 -
The EMBO Journal Aug 2016Cells contain numerous, molecularly distinct cellular compartments that are not enclosed by lipid bilayers. These compartments are implicated in a wide range of cellular... (Review)
Review
Cells contain numerous, molecularly distinct cellular compartments that are not enclosed by lipid bilayers. These compartments are implicated in a wide range of cellular activities, and they have been variously described as bodies, granules, or organelles. Recent evidence suggests that a liquid-liquid phase separation (LLPS) process may drive their formation, possibly justifying the unifying term "droplet organelle". A veritable deluge of recent publications points to the importance of low-complexity proteins and RNA in determining the physical properties of phase-separated structures. Many of the proteins linked to such structures are implicated in human diseases, such as amyotrophic lateral sclerosis (ALS). We provide an overview of the organizational principles that characterize putative "droplet organelles" in healthy and diseased cells, connecting protein biochemistry with cell physiology.
Topics: Cell Physiological Phenomena; Cytosol; Macromolecular Substances; Multienzyme Complexes
PubMed: 27357569
DOI: 10.15252/embj.201593517 -
Current Biology : CB Jul 2019In 1955, the biologist and Nobel Prize laureate Christian de Duve discovered that cells possess specialized organelles filled with hydrolytic enzymes and he called these...
In 1955, the biologist and Nobel Prize laureate Christian de Duve discovered that cells possess specialized organelles filled with hydrolytic enzymes and he called these organelles lysosomes. At the same time, electron microscopy studies by Novikoff and colleagues showed that intracellular dense bodies, which later turned out to be lysosomes, contain cytoplasmic components. Together, these groundbreaking observations revealed that cells can deliver cytoplasmic components to lysosomes for degradation. The hallmark of this degradative process, which de Duve called autophagy, is the formation of double-membrane-limited vesicles. Further morphological characterization of these vesicles (autophagosomes) revealed that they mainly contain bulk cytoplasm. Although this suggested that autophagy leads to a non-selective degradation of cytoplasmic material, de Duve anticipated that a regulated and selective type of this pathway must also exist. Today we know that, under normal conditions, macroautophagy is a highly selective pathway that sequesters damaged or superfluous material from the cytoplasm through the formation of double-membrane-limited autophagosomes. Upon fusion with lysosomes, the content of autophagosomes is degraded and the resulting building blocks are released into the cytoplasm. However, in response to cytotoxic stress or starvation, cells start to produce autophagosomes that capture bulk cytoplasm non-selectively. This stress response is essential for cells to survive adverse environmental conditions, whereas the selective sequestration of cargo is important to maintain cellular homeostasis.
Topics: Autophagosomes; Autophagy; Cytosol; Lysosomes; Macroautophagy
PubMed: 31336079
DOI: 10.1016/j.cub.2019.06.014 -
Nature Materials May 2023The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a...
The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.
Topics: Actins; DNA; Nucleotidyltransferases; Cytosol; Signal Transduction; Neoplasms
PubMed: 36581770
DOI: 10.1038/s41563-022-01431-x -
Chimia May 2019Besides their medical importance, the parasitic protozoan and its relatives are experimentally highly accessible model systems for many cell biological processes.... (Review)
Review
Besides their medical importance, the parasitic protozoan and its relatives are experimentally highly accessible model systems for many cell biological processes. Trypanosomes are phylogenetically essentially unrelated to the popular model eukaryotes, such as yeast and animals, and thus show several unique features, many of which are connected to RNA. Here we review the tRNA biology of trypanosomes. Even though tRNAs were already discovered 60 years ago, owing to current technological advances in the field, research on tRNA biology has seen a Renaissance in recent years. First we discuss the extensive mitochondrial tRNA import process and the consequences it has for the parasite. Next we focus on trypanosomal aminoacyl-tRNA synthetases, some of which may be exploited as drug targets. Furthermore, we summarize what is known about trypanosomal tRNA modifications in both the cytosol and the mitochondrion. Finally, we provide an overview on the emerging field of tRNA-derived fragments and their possible function as translation regulators.
Topics: Animals; Cytosol; Mitochondria; RNA, Transfer; Trypanosoma
PubMed: 31118122
DOI: 10.2533/chimia.2019.395 -
Nature Mar 2020Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is compromised in ageing and various pathologies. Mitochondrial malfunction needs to be...
Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is compromised in ageing and various pathologies. Mitochondrial malfunction needs to be relayed to the cytosol, where an integrated stress response is triggered by the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) in mammalian cells. eIF2α phosphorylation is mediated by the four eIF2α kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress. However, the machinery that communicates mitochondrial perturbation to the cytosol to trigger the integrated stress response remains unknown. Here we combine genome engineering and haploid genetics to unbiasedly identify genes that affect the induction of C/EBP homologous protein (CHOP), a key factor in the integrated stress response. We show that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. Obstruction of this pathway can be beneficial or adverse depending on the type of mitochondrial perturbation. In addition to the core pathway components, our comparative genetic screening strategy identifies a suite of additional regulators. Together, these findings could be used to inform future strategies to modulate the cellular response to mitochondrial dysfunction in the context of human disease.
Topics: Cytosol; Enzyme Activation; Eukaryotic Initiation Factor-2; Genome, Human; Humans; Metalloendopeptidases; Mitochondria; Mitochondrial Proteins; Phosphorylation; Protein Binding; Stress, Physiological; Transcription Factor CHOP; eIF-2 Kinase
PubMed: 32132706
DOI: 10.1038/s41586-020-2076-4 -
Nature May 2021Mycobacterium tuberculosis is the cause of one of the most important infectious diseases in humans, which leads to 1.4 million deaths every year. Specialized protein...
Mycobacterium tuberculosis is the cause of one of the most important infectious diseases in humans, which leads to 1.4 million deaths every year. Specialized protein transport systems-known as type VII secretion systems (T7SSs)-are central to the virulence of this pathogen, and are also crucial for nutrient and metabolite transport across the mycobacterial cell envelope. Here we present the structure of an intact T7SS inner-membrane complex of M. tuberculosis. We show how the 2.32-MDa ESX-5 assembly, which contains 165 transmembrane helices, is restructured and stabilized as a trimer of dimers by the MycP protease. A trimer of MycP caps a central periplasmic dome-like chamber that is formed by three EccB dimers, with the proteolytic sites of MycP facing towards the cavity. This chamber suggests a central secretion and processing conduit. Complexes without MycP show disruption of the EccB periplasmic assembly and increased flexibility, which highlights the importance of MycP for complex integrity. Beneath the EccB-MycP chamber, dimers of the EccC ATPase assemble into three bundles of four transmembrane helices each, which together seal the potential central secretion channel. Individual cytoplasmic EccC domains adopt two distinctive conformations that probably reflect different secretion states. Our work suggests a previously undescribed mechanism of protein transport and provides a structural scaffold to aid in the development of drugs against this major human pathogen.
Topics: Cryoelectron Microscopy; Cytosol; Models, Molecular; Mycobacterium tuberculosis; Periplasm; Protein Domains; Protein Multimerization; Protein Stability; Tuberculosis; Type VII Secretion Systems
PubMed: 33981042
DOI: 10.1038/s41586-021-03517-z