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Proteotoxicity

About: Proteotoxicity is a research topic. Over the lifetime, 549 publications have been published within this topic receiving 23151 citations.


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Journal ArticleDOI
TL;DR: Accumulating evidence has recently suggested a pivotal role for proteotoxicity, the unfavorable effects of poor protein quality control, in the pathophysiology of metabolic dysregulation and related cardiovascular complications, and autophagy offers promising targets for novel strategies to prevent and treat cardiorenal metabolic diseases.

90 citations

Journal ArticleDOI
TL;DR: It is shown here that inhibition of proteasomal degradation results in an increased oligomerization and activation of caspase-8 on the cytosolic side of intracellular membranes.
Abstract: The accumulation of damaged or misfolded proteins, if unresolved, can lead to a detrimental consequence within cells termed proteotoxicity. Since cancerous cells often display elevated protein synthesis and by-product disposal, inhibition of the protein degradation pathways is an emerging approach for cancer therapy. However, the molecular mechanism underlying proteotoxicity remains largely unclear. We show here that inhibition of proteasomal degradation results in an increased oligomerization and activation of caspase-8 on the cytosolic side of intracellular membranes. This enhanced caspase-8 oligomerization and activation are promoted through its interaction with the ubiquitin-binding protein SQSTM1/p62 and the microtubule-associated protein light chain 3 (LC3), which are enriched at intracellular membranes in response to proteotoxic stress. Silencing LC3 by shRNA, or the LC3 mutants defective in membrane localization or p62 interaction fail to induce caspase-8 activation and apoptosis. Our results unveiled a previously unknown mechanism through which disruption of protein homeostasis induces caspase-8 oligomerization, activation, and apoptosis.

90 citations

Journal ArticleDOI
TL;DR: The data accumulated demonstrate that spatial quality control involves factors beyond the canonical quality control factors, such as chaperones and proteases, and opens up new venues in approaching how proteotoxicity might be mitigated, or delayed, upon aging.
Abstract: The accumulation of damaged and aggregated proteins is a hallmark of aging and increased proteotoxic stress. To limit the toxicity of damaged and aggregated proteins and to ensure that the damage is not inherited by succeeding cell generations, a system of spatial quality control operates to sequester damaged/aggregated proteins into inclusions at specific protective sites. Such spatial sequestration and asymmetric segregation of damaged proteins have emerged as key processes required for cellular rejuvenation. In this review, we summarize findings on the nature of the different quality control sites identified in yeast, on genetic determinants required for spatial quality control, and on how aggregates are recognized depending on the stress generating them. We also briefly compare the yeast system to spatial quality control in other organisms. The data accumulated demonstrate that spatial quality control involves factors beyond the canonical quality control factors, such as chaperones and proteases, and opens up new venues in approaching how proteotoxicity might be mitigated, or delayed, upon aging.

89 citations

Journal ArticleDOI
TL;DR: Among many signalling mechanisms involved in altering longevity and aging, the insulin/IGF-1 pathway and the Sir2 deacetylase are highly significant and an enquires into the role of some of these pathways in longevity/aging along with HSP.
Abstract: Heat shock proteins (HSP) are molecular chaperones and have been implicated in longevity and aging in many species. Their major functions include chaperoning misfolded or newly synthesised polypeptides, protecting cells from proteotoxic stress, and processing of immunogenic agents. These proteins are expressed constitutively and can be induced by stresses such as heat, oxidative stress and many more. The induction of HSP in aging could potentially maintain protein homeostasis and longevity by refolding the damaged proteins which accumulate during aging and are toxic to cells. HSP are shown to increase life span in model organisms such as Caenorhabditis elegans and decrease aging-related proteotoxicity. Thus, decrease in HSP in aging is associated with disruption of cellular homeostasis which causes diseases such as cancer, cell senescence and neurodegeneration. HSP levels are decreased with aging in most organs including neurons. Aging also causes attenuation or alteration of many signalling pathw...

88 citations

Journal ArticleDOI
TL;DR: It is proposed that this strategy to enhance cell stress pathways and chaperone activity establishes a cytoprotective state against misfolding and/or aggregation and represents a promising therapeutic avenue to prevent the cellular damage associated with the variety of protein conformational diseases.
Abstract: Protein misfolding and aggregation are widely implicated in an increasing number of human diseases providing for new therapeutic opportunities targeting protein homeostasis (proteostasis). The cellular response to proteotoxicity is highly regulated by stress signaling pathways, molecular chaperones, transport and clearance machineries that function as a proteostasis network (PN) to protect the stability and functional properties of the proteome. Consequently, the PN is essential at the cellular and organismal level for development and lifespan. However, when challenged during aging, stress, and disease, the folding and clearance machineries can become compromised leading to both gain-of-function and loss-of-function proteinopathies. Here, we assess the role of small molecules that activate the heat shock response, the unfolded protein response, and clearance mechanisms to increase PN capacity and protect cellular proteostasis against proteotoxicity. We propose that this strategy to enhance cell stress pathways and chaperone activity establishes a cytoprotective state against misfolding and/or aggregation and represents a promising therapeutic avenue to prevent the cellular damage associated with the variety of protein conformational diseases.

87 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202327
202262
202166
202065
201950
201832