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Proteostasis

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https://www.readbyqxmd.com/read/29331499/hspb7-is-a-cardioprotective-chaperone-facilitating-sarcomeric-proteostasis
#1
Emily J Mercer, Yi-Fan Lin, Leona Cohen-Gould, Todd Evans
Small heat shock proteins are chaperones with variable mechanisms of action. The function of cardiac family member Hspb7 is unknown, despite being identified through GWAS as a potential cardiomyopathy risk gene. We discovered that zebrafish hspb7 mutants display mild focal cardiac fibrosis and sarcomeric abnormalities. Significant mortality was observed in adult hspb7 mutants subjected to exercise stress, demonstrating a genetic and environmental interaction that determines disease outcome. We identified large sarcomeric proteins FilaminC and Titin as Hspb7 binding partners in cardiac cells...
January 10, 2018: Developmental Biology
https://www.readbyqxmd.com/read/29330040/yod1-attenuates-neurogenic-proteotoxicity-through-its-deubiquitinating-activity
#2
Kunikazu Tanji, Fumiaki Mori, Yasuo Miki, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
Ubiquitination, a fundamental post-translational modification of intracellular proteins, is enzymatically reversed by deubiquitinase enzymes (deubiquitinases). >90 deubiquitinases have been identified. One of these enzymes, YOD1, possesses deubiquitinase activity and is similar to ovarian tumor domain-containing protein 1, which is associated with regulation of the endoplasmic reticulum (ER)-associated degradation pathway. Indeed, YOD1 is reported to be involved in the ER stress response induced by mislocalization of unfolded proteins in mammalian cells...
January 10, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29323786/pulmonary-endoplasmic-reticulum-stress-scars-smoke-and-suffocation
#3
REVIEW
Jennifer A Dickens, Elke Malzer, Joseph E Chambers, Stefan J Marciniak
Protein misfolding within the endoplasmic reticulum (ER stress) can be a cause or consequence of pulmonary disease. Mutation of proteins restricted to the alveolar type II pneumocyte can lead to inherited forms of pulmonary fibrosis, but even sporadic cases of pulmonary fibrosis appear to be strongly associated with activation of the unfolded protein response (UPR) and/or the integrated stress response (ISR). Inhalation of smoke can impair protein folding and may be an important cause of pulmonary ER stress...
January 11, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29323280/nucleotide-exchange-factors-fes1-and-hspbp1-mimic-substrate-to-release-misfolded-proteins-from-hsp70
#4
Naveen K C Gowda, Jayasankar M Kaimal, Roman Kityk, Chammiran Daniel, Jobst Liebau, Marie Öhman, Matthias P Mayer, Claes Andréasson
Protein quality control depends on the tight regulation of interactions between molecular chaperones and polypeptide substrates. Substrate release from the chaperone Hsp70 is triggered by nucleotide-exchange factors (NEFs) that control folding and degradation fates via poorly understood mechanisms. We found that the armadillo-type NEFs budding yeast Fes1 and its human homolog HspBP1 employ flexible N-terminal release domains (RDs) with substrate-mimicking properties to ensure the efficient release of persistent substrates from Hsp70...
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29322304/causative-genes-in-amyotrophic-lateral-sclerosis-and-protein-degradation-pathways-a-link-to-neurodegeneration
#5
REVIEW
C Maurel, A Dangoumau, S Marouillat, C Brulard, A Chami, R Hergesheimer, P Corcia, H Blasco, C R Andres, P Vourc'h
Amyotrophic lateral sclerosis (ALS) is a disease caused by the degeneration of motor neurons (MNs) leading to progressive muscle weakness and atrophy. Several molecular pathways have been implicated, such as glutamate-mediated excitotoxicity, defects in cytoskeletal dynamics and axonal transport, disruption of RNA metabolism, and impairments in proteostasis. ALS is associated with protein accumulation in the cytoplasm of cells undergoing neurodegeneration, which is a hallmark of the disease. In this review, we focus on mechanisms of proteostasis, particularly protein degradation, and discuss how they are related to the genetics of ALS...
January 10, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29321322/dengue-virus-selectively-annexes-endoplasmic-reticulum-associated-translation-machinery-as-a-strategy-for-co-opting-host-cell-protein-synthesis
#6
David W Reid, Rafael K Campos, Jessica R Child, Tianli Zheng, Kitti Wing Ki Chan, Shelton S Bradrick, Subhash G Vasudevan, Mariano A Garcia-Blanco, Christopher V Nicchitta
A primary question in Dengue virus (DENV) biology is the molecular strategy for recruitment of host cell protein synthesis machinery. Here we combined cell fractionation, ribosome profiling, and RNA-seq to investigate the subcellular organization of viral genome translation and replication as well as host cell translation and its response to DENV infection. We report that throughout the viral life cycle, DENV (+) and (-) strand RNAs were highly partitioned to the endoplasmic reticulum (ER), identifying the ER as the primary site of DENV translation...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29317520/atm-directs-dna-damage-responses-and-proteostasis-via-genetically-separable-pathways
#7
Ji-Hoon Lee, Michael R Mand, Chung-Hsuan Kao, Yi Zhou, Seung W Ryu, Alicia L Richards, Joshua J Coon, Tanya T Paull
The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. We genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. We found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage...
January 9, 2018: Science Signaling
https://www.readbyqxmd.com/read/29316491/presynaptic-endocytic-factors-in-autophagy-and-neurodegeneration
#8
REVIEW
Domenico Azarnia Tehran, Marijn Kuijpers, Volker Haucke
Neuronal signaling depends on the exocytic fusion and subsequent endocytic retrieval and reformation of neurotransmitter-containing synaptic vesicles at synapses. Recent findings have uncovered surprising roles of presynaptic endocytic proteins in the formation and transport of autophagosomes. These include functions of the membrane remodelling protein endophilin and its downstream effector, the phosphoinositide phosphatase synaptojanin, in autophagosome formation and in Parkinson's disease, the endocytic sorting adaptor CALM in protein degradation via the autophagy/lysosomal pathway in Alzheimer's disease, and the clathrin adaptor complex AP-2 in retrograde transport of signaling autophagosomes to prevent neurodegeneration...
January 6, 2018: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/29312526/amyotrophic-lateral-sclerosis-as-a-protein-level-non-genomic-disease-therapy-with-s2rm-exosome-released-molecules
#9
REVIEW
Greg Maguire
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that leads to death. No effective treatments are currently available. Based on data from epidemiological, etiological, laboratory, and clinical studies, I offer a new way of thinking about ALS and its treatment. This paper describes a host of extrinsic factors, including the exposome, that disrupt the extracellular matrix and protein function such that a spreading, prion-like disease leads to neurodegeneration in the motor tracts...
November 26, 2017: World Journal of Stem Cells
https://www.readbyqxmd.com/read/29311133/dual-ire1-rnase-functions-dictate-glioblastoma-development
#10
Stéphanie Lhomond, Tony Avril, Nicolas Dejeans, Konstantinos Voutetakis, Dimitrios Doultsinos, Mari McMahon, Raphaël Pineau, Joanna Obacz, Olga Papadodima, Florence Jouan, Heloise Bourien, Marianthi Logotheti, Gwénaële Jégou, Néstor Pallares-Lupon, Kathleen Schmit, Pierre-Jean Le Reste, Amandine Etcheverry, Jean Mosser, Kim Barroso, Elodie Vauléon, Marion Maurel, Afshin Samali, John B Patterson, Olivier Pluquet, Claudio Hetz, Véronique Quillien, Aristotelis Chatziioannou, Eric Chevet
Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes...
January 8, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29303785/mechanisms-of-disordered-neurodegenerative-function-concepts-and-facts-about-the-different-roles-of-the-protein-kinase-rna-like-endoplasmic-reticulum-kinase-perk
#11
Yasmeen M Taalab, Nour Ibrahim, Ahmed Maher, Mubashir Hassan, Wael Mohamed, Ahmed A Moustafa, Mohamed Salama, Dina Johar, Larry Bernstein
Neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis...
January 5, 2018: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/29290985/ophiobolin-a-kills-human-glioblastoma-cells-by-inducing-endoplasmic-reticulum-stress-via-disruption-of-thiol-proteostasis
#12
In Young Kim, MiRi Kwon, Min-Koo Choi, Dongjoo Lee, Dong Min Lee, Min Ji Seo, Kyeong Sook Choi
Ophiobolin A (OP-A), a fungal sesterterpene from Bipolaris oryzae, was recently shown to have anti-glioma activity. We show here that OP-A induces paraptosis-like cell death accompanied by dilation of the endoplasmic reticulum (ER) in glioma cells, and that CHOP-mediated ER stress plays a critical role in this process. OP-A-induced ER-derived dilation and cell death were found to be independent of reactive oxygen species, but were effectively blocked by various thiol antioxidants. We observed that OP-A can react with cysteinyl thiols to form Michael adducts, suggesting that the ability of OP-A to covalently modify free sulfhydryl groups on proteins may cause protein misfolding and the accumulation of misfolded proteins, leading to paraptosis-like cell death...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29290589/ccpg1-is-a-non-canonical-autophagy-cargo-receptor-essential-for-er-phagy-and-pancreatic-er-proteostasis
#13
Matthew D Smith, Margaret E Harley, Alain J Kemp, Jimi Wills, Martin Lee, Mark Arends, Alex von Kriegsheim, Christian Behrends, Simon Wilkinson
Mechanisms of selective autophagy of the ER, known as ER-phagy, require molecular delineation, particularly in vivo. It is unclear how these events control ER proteostasis and cellular health. Here, we identify cell-cycle progression gene 1 (CCPG1), an ER-resident protein with no known physiological role, as a non-canonical cargo receptor that directly binds to core autophagy proteins via an LIR motif to mammalian ATG8 proteins and, independently and via a discrete motif, to FIP200. These interactions facilitate ER-phagy...
December 27, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29274917/autophagy-and-proteostasis-in-the-control-of-synapse-aging-and-disease
#14
REVIEW
YongTian Liang, Stephan Sigrist
The maintenance of neuronal homeostasis is severely threatened by aging, probably partially due to compromised autophagic clearance. Hence, rejuvenating autophagy in aging neurons is considered a promising strategy to restore cognitive performance. Research in recent years has shown that autophagosome biogenesis takes place mainly in distal axons and, thus, close to presynaptic specializations, and that efficient macro-autophagy is essential for neuronal homeostasis and survival. Retrograde transport of autophagosomes might play a role in neuronal signaling processes, promoting neuronal complexity and preventing neurodegeneration...
December 21, 2017: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/29260915/-off-targeting-perk-signaling-the-race-toward-intervening-er-proteostasis
#15
Rodrigo Perez, Alexis Rivas, Claudio Hetz
No abstract text is available yet for this article.
December 20, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29247619/a-new-drosophila-model-of-ubiquilin-knockdown-shows-the-effect-of-impaired-proteostasis-on-locomotive-and-learning-abilities
#16
Salinee Jantrapirom, Luca Lo Piccolo, Hideki Yoshida, Masamitsu Yamaguchi
Ubiquilin (UBQLN) plays a crucial role in cellular proteostasis through its involvement in the ubiquitin proteasome system and autophagy. Mutations in the UBQLN2 gene have been implicated in amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal lobar dementia (ALS/FTLD). Previous studies reported a key role for UBQLN in Alzheimer's disease (AD); however, the mechanistic involvement of UBQLN in other neurodegenerative diseases remains unclear. The genome of Drosophila contains a single UBQLN homolog (dUbqn) that shows high similarity to UBQLN1 and UBQLN2; therefore, the fly is a useful model for characterizing the role of UBQLN in vivo in neurological disorders affecting locomotion and learning abilities...
December 13, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/29247078/high-capacity-of-the-endoplasmic-reticulum-to-prevent-secretion-and-aggregation-of-amyloidogenic-proteins
#17
Lisa Vincenz-Donnelly, Hauke Holthusen, Roman Körner, Erik C Hansen, Jenny Presto, Jan Johansson, Ritwick Sawarkar, F Ulrich Hartl, Mark S Hipp
Protein aggregation is associated with neurodegeneration and various other pathologies. How specific cellular environments modulate the aggregation of disease proteins is not well understood. Here, we investigated how the endoplasmic reticulum (ER) quality control system handles β-sheet proteins that were designed de novo to form amyloid-like fibrils. While these proteins undergo toxic aggregation in the cytosol, we find that targeting them to the ER (ER-β) strongly reduces their toxicity. ER-β is retained within the ER in a soluble, polymeric state, despite reaching very high concentrations exceeding those of ER-resident molecular chaperones...
December 15, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29240668/heat-shock-proteins-in-vascular-diabetic-complications-review-and-future-perspective
#18
REVIEW
Stefania Bellini, Federica Barutta, Raffaella Mastrocola, Luigi Imperatore, Graziella Bruno, Gabriella Gruden
Heat shock proteins (HSPs) are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury...
December 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29240643/temporally-distinct-regulation-of-pathways-contributing-to-cardiac-proteostasis-during-the-acute-and-recovery-phases-of-sepsis
#19
Kristen T Crowell, Samantha Moreno, Jennifer L Steiner, Catherine S Coleman, David I Soybel, Charles H Lang
BACKGROUND: Cardiac dysfunction is a common manifestation of sepsis and is associated with early increases in inflammation and decreases in myocardial protein synthesis. However, little is known regarding the molecular mechanisms regulating protein homeostasis during the recovery phase after the removal of the septic nidus. Therefore, the purpose of this study was to investigate diverse signal transduction pathways that regulate myocardial protein synthesis and degradation. METHODS: Adult male C57BL/6 mice were used to identify potential mechanisms mediating the acute (24 h) effect of cecal ligation and puncture (CLP) as well as long-term changes that manifest during the chronic (10 d) recovery phase...
December 13, 2017: Shock
https://www.readbyqxmd.com/read/29239314/taking-out-the-garbage-cathepsin-d-and-calcineurin-in-neurodegeneration
#20
REVIEW
Andreas Aufschnaiter, Verena Kohler, Sabrina Büttner
Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases...
November 2017: Neural Regeneration Research
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