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Proteostasis

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https://www.readbyqxmd.com/read/28088524/possible-roles-of-the-transcription-factor-nrf1-nfe2l1-in-neural-homeostasis-by-regulating-the-gene-expression-of-deubiquitinating-enzymes
#1
Hiroaki Taniguchi, Shota Okamuro, Misaki Kohji, Tsuyoshi Waku, Kaori Kubo, Atsushi Hatanaka, Yimeng Sun, A M Masudul Azad Chowdhury, Akiyoshi Fukamizu, Akira Kobayashi
The transcription factor Nrf1 (NFE2L1) maintains protein homeostasis (proteostasis) by regulating the gene expression of proteasome subunits in response to proteasome inhibition. The deletion of the Nrf1 gene in neural stem/progenitor cells causes severe neurodegeneration due to the accumulation of ubiquitinated proteins in Purkinje cells and motor neurons (Nrf1 NKO mice). However, the molecular mechanisms governing this neurodegenerative process remain unclear. We demonstrate herein that the loss of Nrf1 leads to the reduced gene expression of the deubiquitinating enzymes (DUBs) but not proteasome subunits in Nrf1 NKO mice between P7 and P18...
January 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28079883/cysteamine-re-establishes-the-clearance-of-pseudomonas-aeruginosa-by-macrophages-bearing-the-cystic-fibrosis-relevant-f508del-cftr-mutation
#2
Eleonora Ferrari, Romina Monzani, Valeria R Villella, Speranza Esposito, Francesca Saluzzo, Federica Rossin, Manuela D'Eletto, Antonella Tosco, Fabiola De Gregorio, Valentina Izzo, Maria C Maiuri, Guido Kroemer, Valeria Raia, Luigi Maiuri
Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28075048/the-sti-and-uba-domains-of-ubqln1-are-critical-determinants-of-substrate-interaction-and-proteostasis
#3
Zimple Kurlawala, Parag P Shah, Charmi Shah, Levi J Beverly
There are 5 Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have 3 functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA) and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders ranging from Alzheimer's disease to cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation...
January 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28067773/a-systems-biological-view-of-life-and-death-decision-with-respect-to-endoplasmic-reticulum-stress-the-role-of-perk-pathway
#4
Margita Márton, Anita Kurucz, Beáta Lizák, Éva Margittai, Gábor Bánhegyi, Orsolya Kapuy
Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) leads to the activation of three branches (Protein kinase (RNA)-like endoplasmic reticulum kinase [PERK], Inositol requiring protein 1 [IRE-1] and Activating trascription factor 6 [ATF6], respectively) of unfolded protein response (UPR). The primary role of UPR is to try to drive back the system to the former or a new homeostatic state by self-eating dependent autophagy, while excessive level of ER stress results in apoptotic cell death...
January 5, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28066979/when-proteostasis-goes-bad-protein-aggregation-in-the-cell
#5
REVIEW
Mona Radwan, Rebecca J Wood, Xiaojing Sui, Danny M Hatters
Protein aggregation is a hallmark of the major neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's and motor neuron and is a symptom of a breakdown in the management of proteome foldedness. Indeed, it is remarkable that under normal conditions cells can keep their proteome in a highly crowded and confined space without uncontrollable aggregation. Proteins pose a particular challenge relative to other classes of biomolecules because upon synthesis they must typically follow a complex folding pathway to reach their functional conformation (native state)...
January 9, 2017: IUBMB Life
https://www.readbyqxmd.com/read/28061811/the-nature-and-nurture-of-cell-heterogeneity-accounting-for-macrophage-gene-environment-interactions-with-single-cell-rna-seq
#6
Quin F Wills, Esther Mellado-Gomez, Rory Nolan, Damien Warner, Eshita Sharma, John Broxholme, Benjamin Wright, Helen Lockstone, William James, Mark Lynch, Michael Gonzales, Jay West, Anne Leyrat, Sergi Padilla-Parra, Sarah Filippi, Chris Holmes, Michael D Moore, Rory Bowden
BACKGROUND: Single-cell RNA-Seq can be a valuable and unbiased tool to dissect cellular heterogeneity, despite the transcriptome's limitations in describing higher functional phenotypes and protein events. Perhaps the most important shortfall with transcriptomic 'snapshots' of cell populations is that they risk being descriptive, only cataloging heterogeneity at one point in time, and without microenvironmental context. Studying the genetic ('nature') and environmental ('nurture') modifiers of heterogeneity, and how cell population dynamics unfold over time in response to these modifiers is key when studying highly plastic cells such as macrophages...
January 7, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28057298/amyotrophic-lateral-sclerosis-pathogenesis-converges-on-defects-in-protein-homeostasis-associated-with-tdp-43-mislocalization-and-proteasome-mediated-degradation-overload
#7
G Lin, D Mao, H J Bellen
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects upper and/or lower motor neurons. It usually affects people between the ages of 40-70. The average life expectancy is about 3-5 years after diagnosis and there is no effective cure available. Identification of variants in more than 20 different loci has provided insight into the pathogenic molecular mechanisms mediating disease pathogenesis. In this review, we focus on seven ALS-causing genes: TDP-43, FUS, C9orf72, VCP, UBQLN2, VAPB and SOD-1, which encompass about 90% of the variants causing familial ALS...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/28055010/continued-26s-proteasome-dysfunction-in-mouse-brain-cortical-neurons-impairs-autophagy-and-the-keap1-nrf2-oxidative-defence-pathway
#8
Aslihan Ugun-Klusek, Michael H Tatham, Jamal Elkharaz, Dumitru Constantin-Teodosiu, Karen Lawler, Hala Mohamed, Simon M L Paine, Glen Anderson, R John Mayer, James Lowe, E Ellen Billett, Lynn Bedford
The ubiquitin-proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2...
January 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28042827/bag2-interferes-with-chip-mediated-ubiquitination-of-hsp72
#9
Bianca Schönbühler, Verena Schmitt, Heike Huesmann, Andreas Kern, Martin Gamerdinger, Christian Behl
The maintenance of cellular proteostasis is dependent on molecular chaperones and protein degradation pathways. Chaperones facilitate protein folding, maturation, and degradation, and the particular fate of a misfolded protein is determined by the interaction of chaperones with co-chaperones. The co-factor CHIP (C-terminus of HSP70-inteacting protein, STUB1) ubiquitinates chaperone substrates and directs proteins to the cellular degradation systems. The activity of CHIP is regulated by two co-chaperones, BAG2 and HSPBP1, which are potent inhibitors of the E3 ubiquitin ligase activity...
December 30, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28036392/a-differentiation-transcription-factor-establishes-muscle-specific-proteostasis-in-caenorhabditis-elegans
#10
Yael Bar-Lavan, Netta Shemesh, Shiran Dror, Rivka Ofir, Esti Yeger-Lotem, Anat Ben-Zvi
Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and whether cellular differentiation affects chaperone expression. Our bioinformatics analyses show that the myogenic transcription factor HLH-1 (MyoD) can bind to the promoters of chaperone genes expressed or required for the folding of muscle proteins...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/28035683/nuclear-inclusion-bodies-of-mutant-and-wild-type-p53-in-cancer-a-hallmark-of-p53-inactivation-and-proteostasis-remodeling-by-p53-aggregation
#11
Frederik De Smet, Mirian Saiz Rubio, Daphne Hompes, Evelyne Naus, Greet De Baets, Tobias Langenberg, Mark S Hipp, Bert Houben, Filip Claes, Sarah Charbonneau, Javier Delgado Blanco, Stephane Plaisance, Shakti Ramkissoon, Lori Ramkissoon, Colinda Simons, Piet van den Brandt, Matty Weijenberg, Manon Van England, Sandrina Lambrechts, Frederic Amant, André D'Hoore, Keith L Ligon, Xavier Sagaert, Joost Schymkowitz, Frederic Rousseau
Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders...
December 30, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/28034832/proteasome-activation-enhances-stemness-and-lifespan-of-human-mesenchymal-stem-cells
#12
Marianna Kapetanou, Niki Chondrogianni, Spyros Petrakis, George Koliakos, Efstathios S Gonos
The age-associated decline of adult stem cell function contributes to the physiological failure of homeostasis during aging. The proteasome plays a key role in the maintenance of proteostasis and its failure is associated with various biological phenomena including senescence and aging. Although stem cell biology has attracted intense attention, the role of proteasome in stemness and its age-dependent deterioration remains largely unclear. By employing both Wharton's-Jelly- and Adipose-derived human adult mesenchymal stem cells (hMSCs), we reveal a significant age-related decline in proteasome content and peptidase activities, accompanied by alterations of proteasomal complexes...
December 27, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28031292/protein-kinase-ck2-modulates-hsj1-function-through-phosphorylation-of-the-uim2-domain
#13
Daniele Ottaviani, Oriano Marin, Giorgio Arrigoni, Cinzia Franchin, Jordi Vilardell, Michele Sandre, Wenwen Li, David A Parfitt, Lorenzo A Pinna, Michael E Cheetham, Maria Ruzzene
HSJ1 (DNAJB2), a member of the DNAJ family of molecular chaperones, is a key player in neuronal proteostasis maintenance. It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and facilitates their delivery to the proteasome for degradation. Mutations in the DNAJB2 gene lead to inherited neuropathies such as Charcot-Marie-Tooth type-2, distal hereditary motor neuropathies, spinal muscular atrophy with parkinsonism and the later stages can resemble amyotrophic lateral sclerosis. HSJ1 overexpression can reduce aggregation of neurodegeneration-associated proteins in vitro and in vivo; however, the regulation of HSJ1 function is little understood...
December 28, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28030835/co-targeting-translation-and-proteasome-rapidly-kills-colon-cancer-cells-with-mutant-ras-raf-via-er-stress
#14
Xiangyun Li, Mei Li, Hang Ruan, Wei Qiu, Xiang Xu, Lin Zhang, Jian Yu
Colorectal cancers with mutant RAS/RAF are therapy refractory. Deregulated mRNA translation has become an emerging target in cancer treatment. We recently reported that mTOR inhibitors induce apoptosis via ER stress and the extrinsic pathway upon acute inhibition of the eIF4F complex in colon cancer cells and xenografts, while mutant BRAF600E leads to therapeutic resistance via ERK-mediated Mcl-1 stabilization. In this study, we demonstrated that several other translation inhibitors also activate ER stress and the extrinsic apoptotic pathway...
December 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/28028237/nrf2-mitigates-lrrk2-and-%C3%AE-synuclein-induced-neurodegeneration-by-modulating-proteostasis
#15
Gaia Skibinski, Vicky Hwang, Dale Michael Ando, Aaron Daub, Alicia K Lee, Abinaya Ravisankar, Sara Modan, Mariel M Finucane, Benjamin A Shaby, Steven Finkbeiner
Mutations in leucine-rich repeat kinase 2 (LRRK2) and α-synuclein lead to Parkinson's disease (PD). Disruption of protein homeostasis is an emerging theme in PD pathogenesis, making mechanisms to reduce the accumulation of misfolded proteins an attractive therapeutic strategy. We determined if activating nuclear factor erythroid 2-related factor (Nrf2), a potential therapeutic target for neurodegeneration, could reduce PD-associated neuron toxicity by modulating the protein homeostasis network. Using a longitudinal imaging platform, we visualized the metabolism and location of mutant LRRK2 and α-synuclein in living neurons at the single-cell level...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28011957/effect-of-pulsed-electromagnetic-fields-on-endoplasmic-reticulum-stress
#16
E Keczan, G Keri, G Banhegyi, I Stiller
The maintenance of protein homeostasis in the endoplasmic reticulum (ER) is crucial in cell life. Disruption of proteostasis results in ER stress that activates the unfolded protein response (UPR); a signalling network assigned to manage the accumulated misfolded or unfolded proteins. Prolonged or unresolved ER stress leads to apoptotic cell death that can be the basis of many serious diseases. Our aim was to study the effect of pulsed electromagnetic fields (PEMF), an alternative, non-invasive therapeutic method on ER stressed cell lines...
October 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28000760/mice-lacking-wrb-reveal-differential-biogenesis-requirements-of-tail-anchored-proteins-in-vivo
#17
Jhon Rivera-Monroy, Lena Musiol, Kirsten Unthan-Fechner, Ákos Farkas, Anne Clancy, Javier Coy-Vergara, Uri Weill, Sarah Gockel, Shuh-Yow Lin, David P Corey, Tobias Kohl, Philipp Ströbel, Maya Schuldiner, Blanche Schwappach, Fabio Vilardi
Tail-anchored (TA) proteins are post-translationally inserted into membranes. The TRC40 pathway targets TA proteins to the endoplasmic reticulum via a receptor comprised of WRB and CAML. TRC40 pathway clients have been identified using in vitro assays, however, the relevance of the TRC40 pathway in vivo remains unknown. We followed the fate of TA proteins in two tissue-specific WRB knockout mouse models and found that their dependence on the TRC40 pathway in vitro did not predict their reaction to receptor depletion in vivo...
December 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27997702/impulse-control-disorder-lysosomal-malfunction-and-atp13a2-insufficiency-in-parkinsonism
#18
REVIEW
Jun-Ping Liu, Jianfeng Li, Yanhua Lu, Lihui Wang, Gang Chen
Lysosomal transport of cargos in neurons is essential for neuronal proteostasis, transmission and functional motors and behaviors. Lysosomal malfunction including storage disorders is involved in the pathogenesis of Parkinson's disease (PD). Given the unclear molecular mechanisms of diverse defects in PD phenotypes, especially behavioral deficits, this mini review explores the cellular contexts of PD impulse control disorders and the molecular aspects of lysosomal cross-membrane transports. Focuses are paid to trace metal involvements in α-synuclein assembly in Lewy bodies, the functions and molecular interactions of ATP13A2 as ATPase transporters in lysosomal membranes for cross-membrane trafficking and lysosomal homeostasis, and our current understandings of the neural circuits in ICD...
December 20, 2016: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/27994142/regulatory-module-involving-fgf13-mir-504-and-p53-regulates-ribosomal-biogenesis-and-supports-cancer-cell-survival
#19
Débora R Bublik, Slađana Bursać, Michal Sheffer, Ines Oršolić, Tali Shalit, Ohad Tarcic, Eran Kotler, Odelia Mouhadeb, Yonit Hoffman, Gilad Fuchs, Yishai Levin, Siniša Volarević, Moshe Oren
The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis...
December 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27992581/gadd34-keeps-the-mtor-pathway-inactivated-in-endoplasmic-reticulum-stress-related-autophagy
#20
Marianna Holczer, Gábor Bánhegyi, Orsolya Kapuy
The balance of protein synthesis and proteolysis (i.e. proteostasis) is maintained by a complex regulatory network in which mTOR (mechanistic target of rapamycin serine/threonine kinase) pathway and unfolded protein response are prominent positive and negative actors. The interplay between the two systems has been revealed; however the mechanistic details of this crosstalk are largely unknown. The aim of the present study was to investigate the elements of crosstalk during endoplasmic reticulum stress and to verify the key role of GADD34 in the connection with the mTOR pathway...
2016: PloS One
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