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Proteostasis

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https://www.readbyqxmd.com/read/29789218/does-too-much-magic-lead-to-mitophagy
#1
Mohamed A Eldeeb, Richard P Fahlman
Neurodegeneration-associated hallmarks include an abundance of protein aggregates and amelioration of mitochondrial function. Despite the knowledge of molecular counteracting mechanisms, the molecular dialogue between protein aggregate accumulation and aberrant mitochondrial import is poorly understood. Recent work unraveled a novel role for the mitochondrial import machinery in regulating cytosolic proteostasis.
May 19, 2018: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/29788763/progress-toward-development-of-a-proteostasis-drug-for-myocilin-associated-glaucoma
#2
Dustin Je Huard, Raquel L Lieberman
No abstract text is available yet for this article.
May 23, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29783751/targeting-protein-quality-control-mechanisms-by-natural-products-to-promote-healthy-ageing
#3
REVIEW
Sophia Wedel, Maria Manola, Maria Cavinato, Ioannis P Trougakos, Pidder Jansen-Dürr
Organismal ageing is associated with increased chance of morbidity or mortality and it is driven by diverse molecular pathways that are affected by both environmental and genetic factors. The progression of ageing correlates with the gradual accumulation of stressors and damaged biomolecules due to the time-dependent decline of stress resistance and functional capacity, which eventually compromise cellular homeodynamics. As protein machines carry out the majority of cellular functions, proteome quality control is critical for cellular functionality and is carried out through the curating activity of the proteostasis network (PN)...
May 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29779948/the-eukaryotic-proteome-is-shaped-by-e3-ubiquitin-ligases-targeting-c-terminal-degrons
#4
Itay Koren, Richard T Timms, Tomasz Kula, Qikai Xu, Mamie Z Li, Stephen J Elledge
Degrons are minimal elements that mediate the interaction of proteins with degradation machineries to promote proteolysis. Despite their central role in proteostasis, the number of known degrons remains small, and a facile technology to characterize them is lacking. Using a strategy combining global protein stability (GPS) profiling with a synthetic human peptidome, we identify thousands of peptides containing degron activity. Employing CRISPR screening, we establish that the stability of many proteins is regulated through degrons located at their C terminus...
May 11, 2018: Cell
https://www.readbyqxmd.com/read/29778759/to-adapt-or-not-to-adapt-consequences-of-declining-adaptive-homeostasis-and-proteostasis-with-age
#5
REVIEW
Laura C D Pomatto, Patrick Y Sun, Kelvin J A Davies
Many consequences of ageing can be broadly attributed to the inability to maintain homeostasis. Multiple markers of ageing have been identified, including loss of protein homeostasis, increased inflammation, and declining metabolism. Although much effort has been focused on characterization of the ageing phenotype, much less is understood about the underlying causes of ageing. To address this gap, we outline the age-associated consequences of dysregulation of 'Adaptive Homeostasis' and its proposed contributing role as an accelerator of the ageing phenotype...
May 17, 2018: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/29775273/the-role-of-clpp-protease-in-bacterial-pathogenesis-and-human-diseases
#6
Vaibhav Bhandari, Keith S Wong, Jin Lin Zhou, Mark F Mabanglo, Robert A Batey, Walid A Houry
In prokaryotic cells and eukaryotic organelles, the ClpP protease plays an important role in proteostasis. The disruption of ClpP function has been shown to influence the infectivity and virulence of a number of bacterial pathogens. More recently, ClpP has been found to be involved in various forms of carcinomas and in Perrault syndrome, which is an inherited condition characterized by hearing loss in males and females and by ovarian abnormalities in females. Hence, targeting ClpP is a potentially viable, attractive option for the treatment of different ailments...
May 18, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29771174/signaling-and-induction-of-chaperone-mediated-autophagy-by-the-endoplasmic-reticulum-under-stress-conditions
#7
Wenming Li, Qian Yang, Zixu Mao
Chaperone-mediated autophagy (CMA), a form of selective autophagy, maintains cellular proteostasis in response to diverse stress conditions. Whether and how endoplasmic reticulum (ER) stress triggers CMA remains elusive. In our recent study, we demonstrate that various types of ER stress activate the CMA pathway via an EIF2AK3/PERK-MAP2K4/MKK4-MAPK14/p38-dependent manner. We term this process ERICA for ER stress-induced chaperone-mediated autophagy. This pathway is activated in response to stress associated with Parkinson disease and is required for the viability of the SNc dopaminergic neurons in an animal model of Parkinson disease...
May 17, 2018: Autophagy
https://www.readbyqxmd.com/read/29760078/chaperone-ampylation-modulates-aggregation-and-toxicity-of-neurodegenerative-disease-associated-polypeptides
#8
Matthias C Truttmann, David Pincus, Hidde L Ploegh
Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation, a posttranslational protein modification that has emerged as a powerful modulator of HSP70 activity, influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in Caenorhabditis elegans directly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)-extended polypeptide, and of α-synuclein (α-syn)...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29759483/induction-of-the-immunoproteasome-subunit-lmp7-links-proteostasis-and-immunity-in-%C3%AE-synuclein-aggregation-disorders
#9
Scott Ugras, Malcolm J Daniels, Hossein Fazelinia, Neal S Gould, Anastasia K Yocum, Kelvin C Luk, Esteban Luna, Hua Ding, Chris McKennan, Steven Seeholzer, Dan Martinez, Perry Evans, Daniel Brown, John E Duda, Harry Ischiropoulos
Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling...
May 11, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29754951/mitochondrial-translation-efficiency-controls-cytoplasmic-protein-homeostasis
#10
Tamara Suhm, Jayasankar Mohanakrishnan Kaimal, Hannah Dawitz, Carlotta Peselj, Anna E Masser, Sarah Hanzén, Matevž Ambrožič, Agata Smialowska, Markus L Björck, Peter Brzezinski, Thomas Nyström, Sabrina Büttner, Claes Andréasson, Martin Ott
Cellular proteostasis is maintained via the coordinated synthesis, maintenance, and breakdown of proteins in the cytosol and organelles. While biogenesis of the mitochondrial membrane complexes that execute oxidative phosphorylation depends on cytoplasmic translation, it is unknown how translation within mitochondria impacts cytoplasmic proteostasis and nuclear gene expression. Here we have analyzed the effects of mutations in the highly conserved accuracy center of the yeast mitoribosome. Decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response...
April 24, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29753879/protein-aggregation-in-cell-biology-an-aggregomics-perspective-of-health-and-disease
#11
REVIEW
Dezerae Cox, Candice Raeburn, Xiaojing Sui, Danny M Hatters
Maintaining protein homeostasis (proteostasis) is essential for cellular health and is governed by a network of quality control machinery comprising over 800 genes. When proteostasis becomes imbalanced, proteins can abnormally aggregate or become mislocalized. Inappropriate protein aggregation and proteostasis imbalance are two of the central pathological features of common neurodegenerative diseases including Alzheimer, Parkinson, Huntington, and motor neuron diseases. How aggregation contributes to the pathogenic mechanisms of disease remains incompletely understood...
May 10, 2018: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29753111/irak2-counterbalances-oncogenic-smurf1-in-colon-cancer-cells-by-dictating-er-stress
#12
Jingwen Liu, Yuhan Chen, Qingyang Huang, Wen Liu, Xiqing Ji, Fan Hu, Ying Zhu, Lingqiang Zhang, Guanglong Dong
The endoplasmic reticulum (ER) is a cellular organelle with central roles in maintaining proteostasis. The accumulation of misfolded proteins in the ER lumen causes ER stress. Cells evoke an evolutionarily conserved adaptive signaling network "unfolded protein response" to restore ER homeostasis, however, how the signaling network is delicately orchestrated remains largely unrevealed. Meanwhile, the HECT type E3 ligase Smad ubiquitylation regulatory factor 1 (Smurf1) has been reported to play critical roles in several important biological pathways by targeting distinct substrates for ubiquitylation, including WFS1, a critical mediator of ER stress, whereas the regulation of Smurf1 activity and abundance upon ER stress are poorly understood...
May 9, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29752334/tg2-regulates-the-heat-shock-response-by-the-post-translational-modification-of-hsf1
#13
Federica Rossin, Valeria Rachela Villella, Manuela D'Eletto, Maria Grazia Farrace, Speranza Esposito, Eleonora Ferrari, Romina Monzani, Luca Occhigrossi, Vittoria Pagliarini, Claudio Sette, Giorgio Cozza, Nikolai A Barlev, Laura Falasca, Gian Maria Fimia, Guido Kroemer, Valeria Raia, Luigi Maiuri, Mauro Piacentini
Heat-shock factor 1 (HSF1) is the master transcription factor that regulates the response to proteotoxic stress by controlling the transcription of many stress-responsive genes including the heat-shock proteins. Here, we show a novel molecular mechanism controlling the activation of HSF1. We demonstrate that transglutaminase type 2 (TG2), dependent on its protein disulphide isomerase activity, triggers the trimerization and activation of HSF1 regulating adaptation to stress and proteostasis impairment. In particular, we find that TG2 loss of function correlates with a defect in the nuclear translocation of HSF1 and in its DNA-binding ability to the HSP70 promoter...
May 11, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29744037/endoplasmic-reticulum-turnover-er-phagy-and-other-flavors-in-selective-and-non-selective-er-clearance
#14
REVIEW
Ilaria Fregno, Maurizio Molinari
The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells. It is deputed to lipid and protein biosynthesis, calcium storage, and the detoxification of various exogenous and endogenous harmful compounds. ER activity and size must be adapted rapidly to environmental and developmental conditions or biosynthetic demand. This is achieved on induction of thoroughly studied transcriptional/translational programs defined as "unfolded protein responses" that increase the ER volume and the expression of ER-resident proteins regulating the numerous ER functions...
2018: F1000Research
https://www.readbyqxmd.com/read/29742419/loss-of-proteostasis-is-a-pathomechanism-in-cockayne-syndrome
#15
Marius Costel Alupei, Pallab Maity, Philipp Ralf Esser, Ioanna Krikki, Francesca Tuorto, Rosanna Parlato, Marianna Penzo, Adrian Schelling, Vincent Laugel, Lorenzo Montanaro, Karin Scharffetter-Kochanek, Sebastian Iben
Retarded growth and neurodegeneration are hallmarks of the premature aging disease Cockayne syndrome (CS). Cockayne syndrome proteins take part in the key step of ribosomal biogenesis, transcription of RNA polymerase I. Here, we identify a mechanism originating from a disturbed RNA polymerase I transcription that impacts translational fidelity of the ribosomes and consequently produces misfolded proteins. In cells from CS patients, the misfolded proteins are oxidized by the elevated reactive oxygen species (ROS) and provoke an unfolded protein response that represses RNA polymerase I transcription...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29735657/cotranslocational-processing-of-the-protein-substrate-calmodulin-by-an-aaa-unfoldase-occurs-via-unfolding-and-refolding-intermediates
#16
Rafal Augustyniak, Lewis E Kay
Protein remodeling by AAA+ enzymes is central for maintaining proteostasis in a living cell. However, a detailed structural description of how this is accomplished at the level of the substrate molecules that are acted upon is lacking. Here, we combine chemical cross-linking and methyl transverse relaxation-optimized NMR spectroscopy to study, at atomic resolution, the stepwise unfolding and subsequent refolding of the two-domain substrate calmodulin by the VAT AAA+ unfoldase from Thermoplasma acidophilum By engineering intermolecular disulphide bridges between the substrate and VAT we trap the substrate at different stages of translocation, allowing structural studies throughout the translocation process...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29734798/the-disordered-c-terminus-of-yeast-hsf1-contains-a-cryptic-low-complexity-amyloidogenic-region
#17
Jordi Pujols, Jaime Santos, Irantzu Pallarès, Salvador Ventura
Response mechanisms to external stress rely on networks of proteins able to activate specific signaling pathways to ensure the maintenance of cell proteostasis. Many of the proteins mediating this kind of response contain intrinsically disordered regions, which lack a defined structure, but still are able to interact with a wide range of clients that modulate the protein function. Some of these interactions are mediated by specific short sequences embedded in the longer disordered regions. Because the physicochemical properties that promote functional and abnormal interactions are similar, it has been shown that, in globular proteins, aggregation-prone and binding regions tend to overlap...
May 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29729230/role-of-hypothalamus-in-aging-and-its-underlying-cellular-mechanisms
#18
REVIEW
Keetae Kim, Han Kyoung Choe
Aging is characterized by a progressive loss of several physiological functions that can cause various age-related disorders. Several factors have been identified as causes of aging to elucidate the decline in functions. Various aspects of physiological deterioration are controlled by the hypothalamus, a critical brain region that connects the neuroendocrine system to physiological functions. In addition, functional alterations in a set of agouti-related peptide/neuropeptide Y (AgRP/NPY) and pro-opiomelanocortin (POMC) neurons, a set of growth hormone-releasing hormone (GHRH) and somatostatin (SST) neurons, a set of arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) neurons, and a set of gonadotropin-releasing hormone (GnRH) and kisspeptin/neurokinin B/dynorphin (KNDy) neurons contribute to age-related physiological decline in energy metabolism, hormone regulation, circadian rhythm, and reproduction, respectively...
May 2, 2018: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/29728295/gene-therapy-strategies-to-restore-er-proteostasis-in-disease
#19
REVIEW
Vicente Valenzuela, Kasey L Jackson, Sergio P Sardi, Claudio Hetz
Proteostasis alterations are proposed as a transversal hallmark of several pathological conditions, including metabolic disorders, mechanical injury, cardiac malfunction, neurodegeneration, and cancer. Strategies to improve proteostasis aim to reduce the accumulation of specific disease-related misfolded proteins or bolster the endogenous mechanisms to fold and degrade abnormal proteins. Endoplasmic reticulum (ER) stress is a common pathological signature of a variety of diseases, which engages the unfolded protein response (UPR) as a cellular reaction to mitigate ER stress...
April 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29725981/amyotrophic-lateral-sclerosis-als-and-alzheimer-s-disease-ad-are-characterised-by-differential-activation-of-er-stress-pathways-focus-on-upr-target-genes
#20
L Montibeller, J de Belleroche
The endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR), which is strongly activated in most neurodegenerative disorders. UPR signalling pathways mediated by IRE1α and ATF6 play a crucial role in the maintenance of ER homeostasis through the transactivation of an array of transcription factors. When activated, these transcription factors induce the expression of genes involved in protein folding and degradation with pro-survival effects...
May 4, 2018: Cell Stress & Chaperones
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