Topic
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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TL;DR: This study reported that total water extracts of L. barbarum berry extended lifespan and alleviated toxic protein aggregation in neurodegenerative worms with hsf-1 deficiency and suggested that LBE may be a potential antiaging natural dietary supplement especially to individuals with malnutrition or chronic diseases.
Abstract: Lycium barbarum berry (Ningxia Gouqi, Fructus lycii, goji berry, or wolfberry), as a traditional Chinese herb, was recorded beneficial for longevity in traditional Chinese medical scriptures and currently is a natural dietary supplement worldwide. However, under modern experimental conditions, the longevity effect of L. barbarum berry and the underlying mechanisms have been less studied. Here, we reported that total water extracts of L. barbarum berry (LBE), which contains 22% polysaccharides and other components, such as anthocyanins, extended the lifespan of Caenorhabditis elegans without side effects on worm fertility and pharyngeal pumping. Interestingly, we found that the lifespan extension effect was more prominent in worms with shorter mean lifespan as compared to those with longer mean lifespan. Furthermore, we showed that the lifespan extension effect of LBE depended on deacetylase sir-2.1. Remarkably, LBE rescued heat shock transcription factor-1 (hsf-1) deficiency in wild-type worms with different mean lifespans, and this effect also depended on sir-2.1. In addition, we found that LBE extended lifespan and alleviated toxic protein aggregation in neurodegenerative worms with hsf-1 deficiency. Our study suggested that LBE may be a potential antiaging natural dietary supplement especially to individuals with malnutrition or chronic diseases and a potential therapeutic agent for neurodegenerative diseases characterized by hsf-1 deficiency.
4 citations
TL;DR: A new role for verteporfin is found in the control of colorectal cancer progression through the selective induction of proteotoxicity rather than through inhibition of the transcription cofactor YAP.
Abstract: In this issue of Science Signaling, Zhang et al. find a new role for verteporfin in the control of colorectal cancer progression through the selective induction of proteotoxicity rather than through inhibition of the transcription cofactor YAP. The study further documents the potential strategy of targeting proteostasis to kill cancer cells.
4 citations
Dissertation•
04 May 2016
TL;DR: The scope of this work is to study stress resistance, proteostasis, and aging in Caenorhabditis elegans as a resourceful model, and to manipulate aging to prevent decline in the system’s homeostasis.
Abstract: 5 CHAPTER 1: RELATED LITERATURE 7 1.1. Aging 9 1.1.1. Aging as a regulated process 9 1.1.1.1. In search for a valuable approach to study stress resistance, proteostasis, and aging: Caenorhabditis elegans as a resourceful model 10 1.1.1.2. The insulin/IGF-1 signaling (IIS) pathway 12 1.1.1.3. Does the regulation of aging oppose cumulative damages? 15 1.2. The proteome and its challenges 15 1.2.1. Facing the inevitable or how to maintain a pristine proteome 15 1.2.1.1. The proteostasis network: the chaperone, proteasomal, and autophagic systems 16 1.2.1.2. Cellular stress responses: heat shock response (HSR) and unfolded protein response (UPR) 18 1.3. When the system starts failing: aging, loss of proteostasis, and consequences 20 1.3.1. Aging-dependent decline in the system’s homeostasis: what are the evidences? Can aging be manipulated to prevent this decline? 21 1.3.2. Manipulating aging: what can we expect at the proteostasis level? 22 1.3.3. The alteration of aging is associated with elevated stress resistance 25 1.4. The old paradigm changes: regulation of aging at the organismal level 26 1.4.1. Neuronal regulation of aging 26 1.4.2. Neuron-independent regulation of aging 29 1.5. The scope of this work 32
4 citations
TL;DR: It is proposed that Rv0991c, which is named “Ruc” (redox-regulated protein with unstructured C terminus), represents a founding member of a new chaperone family that protects M. tuberculosis and other species from proteotoxicity during oxidative stress.
Abstract: The bacterial pathogen Mycobacterium tuberculosis is the leading cause of death by an infectious disease among humans. Here, we describe a previously uncharacterized M. tuberculosis protein, Rv0991c, as a molecular chaperone that is activated by oxidation. Rv0991c has homologs in most bacterial lineages and appears to function analogously to the well-characterized Escherichia coli redox-regulated chaperone Hsp33, despite a dissimilar protein sequence. Rv0991c is transcriptionally coregulated with hsp60 and hsp70 chaperone genes in M. tuberculosis, suggesting that Rv0991c functions with these chaperones in maintaining protein quality control. Supporting this hypothesis, we found that, like oxidized Hsp33, oxidized Rv0991c prevents the aggregation of a model unfolded protein in vitro and promotes its refolding by the M. tuberculosis Hsp70 chaperone system. Furthermore, Rv0991c interacts with DnaK and can associate with many other M. tuberculosis proteins. We therefore propose that Rv0991c, which we named “Ruc” (redox-regulated protein with unstructured C terminus), represents a founding member of a new chaperone family that protects M. tuberculosis and other species from proteotoxicity during oxidative stress. IMPORTANCEM. tuberculosis infections are responsible for more than 1 million deaths per year. Developing effective strategies to combat this disease requires a greater understanding of M. tuberculosis biology. As in all cells, protein quality control is essential for the viability of M. tuberculosis, which likely faces proteotoxic stress within a host. Here, we identify an M. tuberculosis protein, Ruc, that gains chaperone activity upon oxidation. Ruc represents a previously unrecognized family of redox-regulated chaperones found throughout the bacterial superkingdom. Additionally, we found that oxidized Ruc promotes the protein-folding activity of the essential M. tuberculosis Hsp70 chaperone system. This work contributes to a growing body of evidence that oxidative stress provides a particular strain on cellular protein stability.
4 citations
TL;DR: The results suggest that quinary structure broadly distinguishes the kinetics of subcellular organization, signal propagation, cytoplasmic inheritance, and proteotoxic activities of low complexity “prion-like” sequences.
Abstract: Protein self-assemblies compartmentalize cellular biochemistry and encode molecular memories; but, they also precipitate incurable degenerative diseases. These activities involve vastly different structures and time scales. Recognizing the dominant role of nucleation in self-assembly kinetics, we hypothesized that quinary structures function, in part, by dictating the energy barrier of nucleation. To investigate, we developed Distributed Amphifluoric FRET (DAmFRET), an approach to characterize protein nucleation in living cells. DAmFRET exploits a photoconvertible fluorophore and heterogeneous levels of expression to quantify a proteins self-assembly as a function of its concentration in living cells. Using DAmFRET, we characterize dozens of self-assembling proteins, and find that structural complexity produces nucleation barriers that kinetically control the proteins cellular activities. Pathological prion-like proteins tended to form metastable condensates, whereas prions with physiological functions did not. Our results suggest that quinary structure broadly distinguishes the kinetics of subcellular organization, signal propagation, cytoplasmic inheritance, and proteotoxicity.
4 citations