Protein quality control: from mechanism to disease

Kampinga, Harm H.; Mayer, Matthias P.; Mogk, Axel

doi:10.1007/s12192-019-01040-9

Cited by 9 publications

(4 citation statements)

References 79 publications

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“…The cells have evolved a complex and interconnected quality control system, called the proteostasis network (PN), to support the integrity and functionality of the proteome under physiological conditions and to protect the proteome against acute stress conditions. The PN consists of chaperones, proteases as well as other specialized molecules ( Mogk et al, 2011 ; Kampinga et al, 2019 ). The importance of proteostasis for the health of the organism ( Balch et al, 2008 ) and the decline of proteostasis during ageing ( Ben-Zvi et al, 2009 ) have been recognized for over a decade.…”

Section: Bacterial Proteostasis Faces Particular Challengesmentioning

confidence: 99%

Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

Khodaparast

Schmidt

et al. 2021

Front. Mol. Biosci.

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Cells have evolved a complex molecular network, collectively called the protein homeostasis (proteostasis) network, to produce and maintain proteins in the appropriate conformation, concentration and subcellular localization. Loss of proteostasis leads to a reduction in cell viability, which occurs to some degree during healthy ageing, but is also the root cause of a group of diverse human pathologies. The accumulation of proteins in aberrant conformations and their aggregation into specific beta-rich assemblies are particularly detrimental to cell viability and challenging to the protein homeostasis network. This is especially true for bacteria; it can be argued that the need to adapt to their changing environments and their high protein turnover rates render bacteria particularly vulnerable to the disruption of protein homeostasis in general, as well as protein misfolding and aggregation. Targeting bacterial proteostasis could therefore be an attractive strategy for the development of novel antibacterial therapeutics. This review highlights advances with an antibacterial strategy that is based on deliberately inducing aggregation of target proteins in bacterial cells aiming to induce a lethal collapse of protein homeostasis. The approach exploits the intrinsic aggregation propensity of regions residing in the hydrophobic core regions of the polypeptide sequence of proteins, which are genetically conserved because of their essential role in protein folding and stability. Moreover, the molecules were designed to target multiple proteins, to slow down the build-up of resistance. Although more research is required, results thus far allow the hope that this strategy may one day contribute to the arsenal to combat multidrug-resistant bacterial infections.

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Section: Bacterial Proteostasis Faces Particular Challengesmentioning

confidence: 99%

Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

Khodaparast

Schmidt

et al. 2021

Front. Mol. Biosci.

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“…Harsh tumor microenvironment (TME) conditions increase intracellular misfolded and damaged proteins; thus, from an evolutionary perspective, cancer adaptability involves proteotoxic stress adaptation. The proteostasis network preserves the proteome functionality by coordinating processes such as protein synthesis and folding, translocation, or degradation, to promptly respond to stress conditions [1,2]. However, severe or persistent stress stimulus can disturb the protein-folding equilibrium and surpass the proteostasis "buffering" capacity, culminating in the induction of cell death.…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Proteins Mediate Intercellular Communications within the Tumor Microenvironment through Extracellular Vesicles

Saito,

Machado,

Lomba

et al. 2024

Applied Biosciences

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From an evolutive perspective, tumor cells endure successive turnover upon stress conditions and pressure to adapt to new environments. These cells use exceptional communication skills to share biological information to “survive upon every metabolic cost”. The tumor microenvironment (TME) is a miscellaneous collection of cells, factors, and extracellular vesicles (EVs). EVs are small lipid bilayer-delimited particles derived from cells with sizes ranging from 100 to 1000 nm. Exosomes (<160 nm) are the minor subtype of EVs, originating from the endosomal pathways. The TME also contains “giant” vesicles, microvesicles (100–1000 nm, MV), originated from membrane blebbing. EVs can act as intercellular communication mediators, contributing to many biological processes, by carrying different biomolecules, such as proteins, lipids, nucleic acids, and metabolites. EV secretion can promote either tumor cell survival or manage their stress to death. Tumor-derived EVs transfer adaptative stress signaling to recipient cells, reprograming these cells. Heat shock proteins (HSP) are prominent stress response regulators, specifically carried by exosomes. HSP-loaded EVs reprogram tumor and TME cells to acquire mechanisms contributing to tumor progression and therapy resistance. The intercellular communication mediated by HSP-loaded EVs favors the escape of tumor cells from the endoplasmic reticulum stress, hypoxia, apoptosis, and anticancer therapies. Extracellular HSPs activate and deactivate the immune response, induce cell differentiation, change vascular homeostasis, and help to augment the pre-metastatic niche formation. Here we explore EVs’ mechanisms of HSP transmission among TME cells and the relevance of these intercellular communications in resistance to therapy.

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“…A spectrum of mechanisms and cellular components are involved in the monitoring and maintenance of cellular proteins under physiological and pathological conditions 2 . The coordinated and cooperative functioning of cellular processes not only ensures that nascent polypeptides are properly folded and assembled into functional complexes, 3 but also provides quality control by channeling the degradation of misfolded, aggregated, and non‐functional proteins 4 . Corrective mechanisms in proteostasis deal with the conformational flexibility and concentration dynamics of proteins under different conditions.…”

Section: Introductionmentioning

confidence: 99%

Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

Pande

Ghosh

2023

The FASEB Journal

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Laminopathies are a group of rare genetic disorders with heterogeneous clinical phenotypes such as premature aging, cardiomyopathy, lipodystrophy, muscular dystrophy, microcephaly, epilepsy, and so on. The cellular phenomena associated with laminopathy invariably show disruption of nucleoskeleton of lamina due to deregulated expression, localization, function, and interaction of mutant lamin proteins. Impaired spatial and temporal tethering of lamin proteins to the lamina or nucleoplasmic aggregation of lamins are the primary molecular events that can trigger nuclear proteotoxicity by modulating differential protein–protein interactions, sequestering quality control proteins, and initiating a cascade of abnormal post‐translational modifications. Clearly, laminopathic cells exhibit moderate to high nuclear proteotoxicity, raising the question of whether an imbalance in nuclear proteostasis is involved in laminopathic diseases, particularly in diseases of early aging such as HGPS and laminopathy‐associated premature aging. Here, we review nuclear proteostasis and its deregulation in the context of lamin proteins and laminopathies.

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Protein quality control: from mechanism to disease

Cited by 9 publications

References 79 publications

Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

Heat Shock Proteins Mediate Intercellular Communications within the Tumor Microenvironment through Extracellular Vesicles

Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

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