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Proteostasis

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https://www.readbyqxmd.com/read/27920251/a-homeostatic-shift-facilitates-endoplasmic-reticulum-proteostasis-through-transcriptional-integration-of-proteostatic-stress-response-pathways
#1
Liam Baird, Tadayuki Tsujita, Eri Kobayashi, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Masayuki Yamamoto
Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Whilst the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system (UPS), which functions to degrade damaged, unfolded or short half-life proteins...
December 5, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27911893/the-mitochondrial-m-aaa-protease-prevents-demyelination-and-hair-greying
#2
Shuaiyu Wang, Julie Jacquemyn, Sara Murru, Paola Martinelli, Esther Barth, Thomas Langer, Carien M Niessen, Elena I Rugarli
The m-AAA protease preserves proteostasis of the inner mitochondrial membrane. It ensures a functional respiratory chain, by controlling the turnover of respiratory complex subunits and allowing mitochondrial translation, but other functions in mitochondria are conceivable. Mutations in genes encoding subunits of the m-AAA protease have been linked to various neurodegenerative diseases in humans, such as hereditary spastic paraplegia and spinocerebellar ataxia. While essential functions of the m-AAA protease for neuronal survival have been established, its role in adult glial cells remains enigmatic...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27896217/adapt-recycle-and-move-on-proteostasis-and-trafficking-mechanisms-in-melanoma
#3
REVIEW
Seyma Demirsoy, Shaun Martin, Hannelore Maes, Patrizia Agostinis
Melanoma has emerged as a paradigm of a highly aggressive and plastic cancer, capable to co-opt the tumor stroma in order to adapt to the hostile microenvironment, suppress immunosurveillance mechanisms, and disseminate. In particular, oncogene- and aneuploidy-driven dysregulations of proteostasis in melanoma cells impose a rewiring of central proteostatic processes, such as the heat shock and unfolded protein responses, autophagy, and the endo-lysosomal system, to avoid proteotoxicity. Research over the past decade has indicated that alterations in key nodes of these proteostasis pathways act in conjunction with crucial oncogenic drivers to increase intrinsic adaptations of melanoma cells against proteotoxic stress, modulate the high metabolic demand of these cancer cells and the interface with other stromal cells, through the heightened release of soluble factors or exosomes...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27892468/somatic-increase-of-cct8-mimics-proteostasis-of-human-pluripotent-stem-cells-and-extends-c-elegans-lifespan
#4
Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, David Vilchez
Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27881664/lipid-disequilibrium-disrupts-er-proteostasis-by-impairing-erad-substrate-glycan-trimming-and-dislocation
#5
Milton To, Clark W H Peterson, Melissa A Roberts, Jessica L Counihan, Tiffany T Wu, Mercedes S Forster, Daniel K Nomura, James A Olzmann
The endoplasmic reticulum (ER) mediates the folding, maturation, and deployment of the secretory proteome. Proteins that fail to achieve their native conformation are retained in the ER and targeted for clearance by ER-associated degradation (ERAD), a sophisticated process that mediates the ubiquitin-dependent delivery of substrates to the 26S proteasome for proteolysis. Recent findings indicate that inhibition of long-chain acyl-CoA synthetases with triacsin C, a fatty acid analog, impairs lipid droplet (LD) biogenesis and ERAD, suggesting a role for LDs in ERAD...
November 23, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27872278/reconstitution-of-a-mycobacterium-tuberculosis-proteostasis-network-highlights-essential-cofactor-interactions-with-chaperone-dnak
#6
Tania J Lupoli, Allison Fay, Carolina Adura, Michael S Glickman, Carl F Nathan
During host infection, Mycobacterium tuberculosis (Mtb) encounters several types of stress that impair protein integrity, including reactive oxygen and nitrogen species and chemotherapy. The resulting protein aggregates can be resolved or degraded by molecular machinery conserved from bacteria to eukaryotes. Eukaryotic Hsp104/Hsp70 and their bacterial homologs ClpB/DnaK are ATP-powered chaperones that restore toxic protein aggregates to a native folded state. DnaK is essential in Mycobacterium smegmatis, and ClpB is involved in asymmetrically distributing damaged proteins during cell division as a mechanism of survival in Mtb, commending both proteins as potential drug targets...
November 21, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27864315/protein-quality-control-in-health-and-disease
#7
Tatyana Dubnikov, Tziona Ben-Gedalya, Ehud Cohen
Maintaining functional protein homeostasis (proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP)...
November 18, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27863501/mutations-in-lrrk2-impair-nf-%C3%AE%C2%BAb-pathway-in-ipsc-derived-neurons
#8
Rakel López de Maturana, Valérie Lang, Amaia Zubiarrain, Amaya Sousa, Nerea Vázquez, Ana Gorostidi, Julio Águila, Adolfo López de Munain, Manuel Rodríguez, Rosario Sánchez-Pernaute
BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinson's disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2. METHODS: Taking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2(G2019S) and LRRK2(R1441G) mutations...
November 18, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27856431/endoplasmic-reticulum-proteostasis-a-key-checkpoint-in-cancer
#9
Scott A Oakes
The unfolded protein response (UPR) is an intracellular signaling network largely controlled by three endoplasmic reticulum (ER) transmembrane proteins-IRE1, PERK, and ATF6-that monitors the protein folding status of the ER and initiates corrective measures to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins--conditions often encountered by cancer cells-can lead to the accumulation of misfolded proteins in the ER and cause "ER stress...
November 16, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27846716/-mechanisms-of-protein-homeostasis-regulation-in-cancer-development
#10
F Trčka, P Müller, B Vojtěšek
BACKGROUND: The proteome of eukaryotic cells represents a complex system. Its components are exposed to various intrinsic and extrinsic stresses. Therefore, the function of the cellular proteome is dependent on the existence of compensatory mechanisms balancing the inner protein homeostasis - proteostasis. These mechanisms involve the network of molecular chaperones and transcriptional program regulating their expression. The process of cancerogenesis is accompanied by significant changes in the intracellular milieu of cancer cells - temperature, pH, availability of nutrients...
2016: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/27846364/hsf1-stress-response-pathway-regulates-autophagy-receptor-sqstm1-p62-associated-proteostasis
#11
Yoshihisa Watanabe, Atsushi Tsujimura, Katsutoshi Taguchi, Masaki Tanaka
Proteostasis is important for protecting cells from harmful proteins and is mainly controlled by the HSF1 (heat shock transcription factor 1) stress response pathway. This pathway facilitates protein refolding by molecular chaperones; however, it is unclear whether it functions in autophagy or inclusion formation. The autophagy receptor SQSTM1/p62 is involved in selective autophagic clearance and inclusion formation by harmful proteins, and its phosphorylation at S349, S403, and S407 is required for binding to substrates...
November 15, 2016: Autophagy
https://www.readbyqxmd.com/read/27845970/role-of-the-unfolded-protein-response-in-tumor-cell-characteristics-and-cancer-outcome
#12
Antoine Galmiche, Chloé Sauzay, Eric Chevet, Olivier Pluquet
PURPOSE OF REVIEW: In the present review, we discuss the possible role of the unfolded protein response (UPR) in the acquisition of tumor cell characteristics and in the prognosis of cancer outcome, which could assist and contribute to the development of more promising therapeutic strategies. RECENT FINDINGS: Accumulating evidence supports the idea that alteration of endoplasmic reticulum proteostasis is a key player in cancer development and aggressiveness. Some UPR components were reported as independent prognostic biomarker...
January 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/27832521/a-central-role-for-phosphorylated-p38%C3%AE-in-linking-proteasome-inhibition-induced-apoptosis-and-autophagy
#13
Fang Guo, Xi-Biao He, Song Li, Weidong Le
Autophagy and the ubiquitin proteasome system (UPS), as two major protein degradation pathways, coordinate with each other in regulating programmed cell death. Autophagy can compensate for the UPS impairment-induced cell dysfunction and apoptosis. However, it is not clear how cells maintain the delicate balance between UPS-related apoptosis and autophagy. Here, we showed that proteasome inhibition-mediated UPS impairment can activate the phosphorylated p38α (p-p38α)-dependent apoptotic pathway and autophagy pathway in both neuroblastoma cell line N2a and primary cortical neuronal cells...
November 10, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27831465/dynamic-control-of-hsf1-during-heat-shock-by-a-chaperone-switch-and-phosphorylation
#14
Xu Zheng, Joanna Krakowiak, Nikit Patel, Ali Beyzavi, Jideofor Ezike, Ahmad S Khalil, David Pincus
Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70...
November 10, 2016: ELife
https://www.readbyqxmd.com/read/27821780/quantitative-determination-of-ribosome-nascent-chain-stability
#15
Avi J Samelson, Madeleine K Jensen, Randy A Soto, Jamie H D Cate, Susan Marqusee
Accurate protein folding is essential for proper cellular and organismal function. In the cell, protein folding is carefully regulated; changes in folding homeostasis (proteostasis) can disrupt many cellular processes and have been implicated in various neurodegenerative diseases and other pathologies. For many proteins, the initial folding process begins during translation while the protein is still tethered to the ribosome; however, most biophysical studies of a protein's energy landscape are carried out in isolation under idealized, dilute conditions and may not accurately report on the energy landscape in vivo...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27821326/effects-of-transgenic-methionine-sulfoxide-reductase-a-msra-expression-on-lifespan-and-age-dependent-changes-in-metabolic-function-in-mice
#16
Adam B Salmon, Geumsoo Kim, Chengyu Liu, Jonathan D Wren, Constantin Georgescu, Arlan Richardson, Rodney L Levine
Mechanisms that preserve and maintain the cellular proteome are associated with long life and healthy aging. Oxidative damage is a significant contributor to perturbation of proteostasis and is dealt with by the cell through regulation of antioxidants, protein degradation, and repair of oxidized amino acids. Methionine sulfoxide reductase A (MsrA) repairs oxidation of free- and protein-bound methionine residues through enzymatic reduction and is found in both the cytosol and the mitochondria. Previous studies in Drosophila have shown that increasing expression of MsrA can extend longevity...
December 2016: Redox Biology
https://www.readbyqxmd.com/read/27818636/mitochondrial-quality-control-in-cardiac-diseases
#17
REVIEW
Juliane C Campos, Luiz H M Bozi, Luiz R G Bechara, Vanessa M Lima, Julio C B Ferreira
Disruption of mitochondrial homeostasis is a hallmark of cardiac diseases. Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for cardiomyocyte survival. In this review, we discuss the most recent findings on the central role of mitochondrial quality control processes including regulation of mitochondrial redox balance, aldehyde metabolism, proteostasis, dynamics, and clearance in cardiac diseases, highlighting their potential as therapeutic targets.
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27818141/hsp90-and-p23-molecular-chaperones-control-chromatin-architecture-by-maintaining-the-functional-pool-of-the-rsc-chromatin-remodeler
#18
Frank J Echtenkamp, Zlata Gvozdenov, Nicholas L Adkins, Yang Zhang, Melinda Lynch-Day, Shinya Watanabe, Craig L Peterson, Brian C Freeman
Molecular chaperones govern protein homeostasis, being allied to the beginning (folding) and ending (degradation) of the protein life cycle. Yet, the Hsp90 system primarily associates with native factors, including fully assembled complexes. The significance of these connections is poorly understood. To delineate why Hsp90 and its cochaperone p23 interact with a mature structure, we focused on the RSC chromatin remodeler. Both Hsp90 and p23 triggered the release of RSC from DNA or a nucleosome. Although Hsp90 only freed bound RSC, p23 enhanced nucleosome remodeling prior to discharging the complex...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27816612/trapping-redox-partnerships-in-oxidant-sensitive-proteins-with-a-small-thiol-reactive-cross-linker
#19
Kristin M Allan, Matthew A Loberg, Juliet Chepngeno, Jennifer E Hurtig, Susmit Tripathi, Min Goo Kang, Jonathan K Allotey, Afton H Widdershins, Jennifer M Pilat, Herbert J Sizek, Wesley J Murphy, Matthew R Naticchia, Joseph B David, Kevin A Morano, James D West
A broad range of redox-regulated proteins undergo reversible disulfide bond formation on oxidation-prone cysteine residues. Heightened reactivity of the thiol groups in these cysteines also increases susceptibility to modification by organic electrophiles, a property that can be exploited in the study of redox networks. Here, we explored whether divinyl sulfone (DVSF), a thiol-reactive bifunctional electrophile, cross-links oxidant-sensitive proteins to their putative redox partners in cells. To test this idea, previously identified oxidant targets involved in oxidant defense (namely, peroxiredoxins, methionine sulfoxide reductases, sulfiredoxin, and glutathione peroxidases), metabolism, and proteostasis were monitored for cross-link formation following treatment of Saccharomyces cerevisiae with DVSF...
November 2, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27815300/prions-chaperones-and-proteostasis-in-yeast
#20
Tatiana A Chernova, Keith D Wilkinson, Yury O Chernoff
Prions are alternatively folded, self-perpetuating protein isoforms involved in a variety of biological and pathological processes. Yeast prions are protein-based heritable elements that serve as an excellent experimental system for studying prion biology. The propagation of yeast prions is controlled by the same Hsp104/70/40 chaperone machinery that is involved in the protection of yeast cells against proteotoxic stress. Ribosome-associated chaperones, proteolytic pathways, cellular quality-control compartments, and cytoskeletal networks influence prion formation, maintenance, and toxicity...
November 4, 2016: Cold Spring Harbor Perspectives in Biology
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