scholarly journals Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

2020 ◽  
Author(s):  
Wouter Huiting ◽  
Steven Bergink
Keyword(s):  
Control Systems ◽  
Genomic Instability ◽  
Therapeutic Strategy ◽  
Protein Quality ◽  
Accelerated Ageing ◽  
Protein Homeostasis ◽  
Vicious Cycle ◽  
Proteotoxic Stress ◽  
Gradual Loss ◽  
Wide Range

AbstractCardiomyopathies, neuropathies, cancer and accelerated ageing are unequivocally distinct diseases, yet they also show overlapping pathological hallmarks, including a gradual loss of genomic integrity and proteotoxic stress. Recent lines of evidence suggest that this overlap could be the result of remarkably interconnected molecular cascades between nuclear genomic instability and a loss of protein homeostasis. In this review, we discuss these complex connections, as well as their possible impact on disease. We focus in particular on the inherent ability of a wide range of genomic alterations to challenge protein homeostasis. In doing so, we provide evidence suggesting that a loss of protein homeostasis could be a far more prevalent consequence of genomic instability than generally believed. In certain cases, such as aneuploidy, a loss of protein homeostasis appears to be a crucial mechanism for pathology, which indicates that enhancing protein quality control systems could be a promising therapeutic strategy in diseases associated with genomic instability.

scholarly journals Salvage NAD+ Biosynthetic Pathway Enzymes Moonlight as Molecular Chaperones to Protect Against Proteotoxicity

2020 ◽  
Author(s):  
Meredith Pinkerton ◽  
Andrea Ruetenik ◽  
Viktoriia Bazylianska ◽  
Eva Nyvltova ◽  
Antoni Barrientos
Keyword(s):  
Control Systems ◽  
Molecular Chaperones ◽  
Biosynthetic Pathway ◽  
Protein Quality ◽  
Cellular Protein ◽  
Salvage Pathway ◽  
Abnormal Protein ◽  
Proteotoxic Stress ◽  
Evolutionarily Conserved ◽  
Hsp90 Chaperone

AbstractHuman neurodegenerative proteinopathies are disorders associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) conditions such as Huntington’s disease (HD) and α-synucleinopathies such as Parkinson’s disease (PD). Overexpression of NMNAT/Nma1, an enzyme in the NAD+ biosynthetic salvage pathway, acts as an efficient suppressor of proteotoxicities in yeast, fly, and mouse models. Screens in yeast models of HD and PD allowed us to identify three additional enzymes of the same pathway that achieve similar protection against proteotoxic stress: Npt1, Pnc1, and Qns1. Here, we report that their ability to maintain proteostasis is independent of their catalytic activity and does not require cellular protein quality control systems such as the proteasome or autophagy. Furthermore, we show that, under proteotoxic stress, the four proteins are recruited as molecular chaperones with holdase and foldase activities. The NAD+ salvage proteins act by preventing misfolding and, together with the Hsp90 chaperone, promoting the refolding of extended polyQ domains or α-synuclein. We conclude that the entire salvage NAD+ biosynthetic pathway links NAD+ metabolism and proteostasis and emerges as a target for therapeutics to combat age-associated neurodegenerative proteotoxicities. Our observations also illustrate the existence of an evolutionarily conserved strategy of repurposing or moonlighting housekeeping enzymes under stress conditions to maintain proteostasis.

scholarly journals Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 66 ◽  
Author(s):  
Matthew Ho Zhi Guang ◽  
Emma L. Kavanagh ◽  
Luke Paul Dunne ◽  
Paul Dowling ◽  
Li Zhang ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Protein Quality ◽  
Hematologic Malignancy ◽  
Cancer Diagnostics ◽  
Protein Homeostasis ◽  
Functional Link ◽  
E3 Ligases ◽  
Proteotoxic Stress ◽  
Cancer Cell Survival ◽  
Integral Role

Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging “Achilles heel” of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation.

scholarly journals Organismal Protein Homeostasis Mechanisms

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 889-901 ◽  
Author(s):  
Thorsten Hoppe ◽  
Ehud Cohen
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Homeostasis ◽  
Control Mechanisms ◽  
Dynamic Regulation ◽  
C Elegans ◽  
Selective Degradation ◽  
Proteotoxic Stress ◽  
Health And Disease ◽  
Folded Proteins

Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a conserved network of quality control pathways that orchestrate the biogenesis of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful proteins by selective degradation. Nevertheless, the proteostasis network has a limited capacity and its collapse deteriorates cellular functionality and organismal viability, causing metabolic, oncological, or neurodegenerative disorders. While cell-autonomous quality control mechanisms have been described intensely, recent work on Caenorhabditis elegans has demonstrated the systemic coordination of proteostasis between distinct tissues of an organism. These findings indicate the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome, opening a new door to define novel therapeutic targets for protein aggregation diseases. Here, we provide an overview of individual protein quality control pathways and the systemic coordination between central proteostatic nodes. We further provide insights into the dynamic regulation of cellular and organismal proteostasis mechanisms that integrate environmental and metabolic changes. The use of C. elegans as a model has pioneered our understanding of conserved quality control mechanisms important to safeguard the organismal proteome in health and disease.

scholarly journals A cullin-RING ubiquitin ligase promotes thermotolerance as part of the Intracellular Pathogen Response in C. elegans

2019 ◽  
Author(s):  
Johan Panek ◽  
Spencer S. Gang ◽  
Kirthi C. Reddy ◽  
Robert J. Luallen ◽  
Amitkumar Fulzele ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Transcriptional Response ◽  
Intracellular Pathogen ◽  
Protein Homeostasis ◽  
Pathogen Infection ◽  
C Elegans ◽  
Proteotoxic Stress ◽  
Expression Of Genes ◽  
Pathogen Response

AbstractIntracellular pathogen infection leads to proteotoxic stress in host organisms. Previously we described a physiological program in the nematode C. elegans called the Intracellular Pathogen Response (IPR), which promotes resistance to proteotoxic stress and appears to be distinct from canonical proteostasis pathways. The IPR is controlled by PALS-22 and PALS-25, proteins of unknown biochemical function, which regulate expression of genes induced by natural intracellular pathogens. We previously showed that PALS-22 and PALS-25 regulate the mRNA expression of the predicted ubiquitin ligase component cullin cul-6, which promotes thermotolerance in pals-22 mutants. However, it was unclear whether CUL-6 acted alone, or together with other ubiquitin ligase components. Here we use co-immunoprecipitation studies paired with genetic analysis to define the cullin-RING ligase components that act together with CUL-6 to promote thermotolerance. First, we identify a previously uncharacterized RING domain protein in the TRIM family we named RCS-1, which acts as a core component with CUL-6 to promote thermotolerance. Next, we show that the Skp-related proteins SKR-3, SKR-4 and SKR-5 act redundantly to promote thermotolerance with CUL-6. Finally, we screened F-box proteins that co-immunoprecipitate with CUL-6 and find that FBXA-158 promotes thermotolerance. In summary, we have defined the three core components and an F-box adaptor of a cullin-RING ligase complex that promotes thermotolerance as part of the IPR in C. elegans, which adds to our understanding of how organisms cope with proteotoxic stress.Significance StatementIntracellular pathogen infection in the nematode Caenorhabditis elegans induces a robust transcriptional response as the host copes with infection. This response program includes several ubiquitin ligase components that are predicted to function in protein quality control. In this study, we show that these infection-induced ubiquitin ligase components form a protein complex that promotes increased tolerance of acute heat stress, an indicator of improved protein homeostasis capacity. These findings show that maintaining protein homeostasis may be a critical component of a multifaceted approach allowing the host to deal with stress caused by intracellular infection.

COMPARISON OF CYBER CRIME AWARENESS AMONG SCIENCE AND SOCIAL SCIENCE PERSPECTIVE TEACHERS

2017 ◽  
Vol 4 (36) ◽  
Author(s):  
Anupam Bansal
Keyword(s):  
Social Science ◽  
Automatic Control ◽  
Control Systems ◽  
Child Pornography ◽  
Cyber Crime ◽  
Computer Data ◽  
Automatic Control Systems ◽  
Living Things ◽  
Wide Range

“Cyber crime” has been used to describe a wide range of offences, including offences against computer data and systems (such as “Hacking”), computer related forgery and fraud (such as “phishing”), content offences (such as disseminating child pornography), and copyright offences (such as the dissemination of pirated content). The word “Cyber Crime” has been derived from the words “Cybernetic” which means the science of communication and automatic control systems in both machines and living things.

scholarly journals Anti-Biofilm Molecules Targeting Functional Amyloids

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 795
Author(s):  
Leticia Matilla-Cuenca ◽  
Alejandro Toledo-Arana ◽  
Jaione Valle
Keyword(s):  
Biofilm Formation ◽  
Therapeutic Strategy ◽  
Research Area ◽  
Therapeutic Strategies ◽  
Structural Components ◽  
Significant Issue ◽  
Wide Range ◽  
Effective Therapeutic Strategy ◽  
Functional Amyloids ◽  
Biofilm Matrix

The choice of an effective therapeutic strategy in the treatment of biofilm-related infections is a significant issue. Amyloids, which have been historically related to human diseases, are now considered to be prevailing structural components of the biofilm matrix in a wide range of bacteria. This assumption creates the potential for an exciting research area, in which functional amyloids are considered to be attractive targets for drug development to dissemble biofilm structures. The present review describes the best-characterized bacterial functional amyloids and focuses on anti-biofilm agents that target intrinsic and facultative amyloids. This study provides a better understanding of the different modes of actions of the anti-amyloid molecules to inhibit biofilm formation. This information can be further exploited to improve the therapeutic strategies to combat biofilm-related infections.

scholarly journals The AAA+ ATPase p97, a cellular multitool

2017 ◽  
Vol 474 (17) ◽  
pp. 2953-2976 ◽  
Author(s):  
Lasse Stach ◽  
Paul S. Freemont
Keyword(s):  
Atp Hydrolysis ◽  
Current Status ◽  
Cellular Functions ◽  
Aaa Atpase ◽  
Cellular Processes ◽  
Proteotoxic Stress ◽  
Binding Domains ◽  
Wide Range ◽  
Aaa Atpases ◽  
Substrate Proteins

The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.

The Influence of In-Vehicle Noise on Speech Recognition for Automotive Voice-Activated Control Systems

2002 ◽  
Vol 33 (9) ◽  
pp. 19-23
Author(s):  
By Dave G. Fish
Keyword(s):  
Speech Recognition ◽  
Control Systems ◽  
Convenient Method ◽  
Vehicle Control ◽  
Climate Control ◽  
High Demand ◽  
Vehicle Noise ◽  
Control Functions ◽  
Wide Range ◽  
Vehicle Systems

Voice activation provides a safe and convenient method of controlling vehicle systems such as in-car entertainment, telecommunications and climate control. In the fullness of time it is likely that there will be a high demand across all vehicle classes for such systems for a wide range of vehicle control functions. One of the challenges facing their development and introduction into vehicles is that of the in-vehicle noise environment.

scholarly journals Cell rounding causes genomic instability by dissociation of single-stranded DNA-binding proteins

2018 ◽  
Author(s):  
Qian Guo ◽  
Xianglu Liao ◽  
Xingwu Wang ◽  
Ling Liu ◽  
Bao Song
Keyword(s):  
Stem Cell ◽  
Dna Binding ◽  
Cell Therapy ◽  
Genomic Instability ◽  
Stem Cell Therapy ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Single Stranded Dna ◽  
Cell Rounding ◽  
Wide Range

AbstractGenomic instability can cause a wide range of diseases, including cancer and cellular senescence, which is also a major challenge in stem cell therapy. However, how a single event can cause extremely high levels of genomic instability remains unclear. Using our developed method, cell in situ electrophoresis (CISE), and models of normal, cancer, and embryonic stem cells, we found that cell rounding as a catastrophic source event ubiquitously observed in vivo and in vitro might lead to large-scale DNA deprotection, genomic instability, chromosomal shattering, cell heterogeneity, and senescent crisis by dissociation of single-stranded DNA-binding proteins (SSBs). Understanding the mechanism may facilitate the development of clinical strategies for cancer therapy, improve the safety of stem cell therapy, and prevent pathological aging.

scholarly journals Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Peter Tsvetkov ◽  
Marc L Mendillo ◽  
Jinghui Zhao ◽  
Jan E Carette ◽  
Parker H Merrill ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Cellular Protein ◽  
Fitness Cost ◽  
Survival Advantage ◽  
Protein Homeostasis ◽  
Proteotoxic Stress ◽  
Genome Wide ◽  
Regulatory Complex ◽  
Modest Reduction ◽  
Specific Inhibitors

Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans.

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