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P97 VCP

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https://www.readbyqxmd.com/read/30010465/loss-of-the-novel-vcp-valosin-containing-protein-interactor-washc4-interferes-with-autophagy-mediated-proteostasis-in-striated-muscle-and-leads-to-myopathy-in-vivo
#1
Monika Kustermann, Linda Manta, Christoph Paone, Jochen Kustermann, Ludwig Lausser, Cora Wiesner, Ludwig Eichinger, Christoph S Clemen, Rolf Schröder, Hans A Kestler, Marco Sandri, Wolfgang Rottbauer, Steffen Just
VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio)...
July 16, 2018: Autophagy
https://www.readbyqxmd.com/read/29967539/structure-of-the-cdc48-atpase-with-its-ubiquitin-binding-cofactor-ufd1-npl4
#2
Nicholas O Bodnar, Kelly H Kim, Zhejian Ji, Thomas E Wales, Vladimir Svetlov, Evgeny Nudler, John R Engen, Thomas Walz, Tom A Rapoport
Many polyubiquitinated proteins are extracted from membranes or complexes by the conserved ATPase Cdc48 (in yeast; p97 or VCP in mammals) before proteasomal degradation. Each Cdc48 hexamer contains two stacked ATPase rings (D1 and D2) and six N-terminal (N) domains. Cdc48 binds various cofactors, including the Ufd1-Npl4 heterodimer. Here, we report structures of the Cdc48-Ufd1-Npl4 complex from Chaetomium thermophilum. Npl4 interacts through its UBX-like domain with a Cdc48 N domain, and it uses two Zn2+ -finger domains to anchor the enzymatically inactive Mpr1-Pad1 N-terminal (MPN) domain, homologous to domains found in several isopeptidases, to the top of the D1 ATPase ring...
July 2, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29941173/altered-expression-of-p97-valosin-containing-protein-and-impaired-autophagy-in-preeclamptic-human-placenta
#3
Asker Zeki Ozsoy, Sevil Cayli, Cansu Sahin, Seda Ocakli, Tuba Ozdemir Sanci, Delibas Bahri Ilhan
INTRODUCTION: Autophagy increases in placenta-related obstetrical diseases such as preeclampsia and intrauterine growth retardation but the regulation of autophagy by ubiquitin proteasome pathway (UPP) proteins, p97/Valosin containing protein (VCP) and ubiquitin (Ub) have not been previuosly studied in preeclampsia. The objective of this study is to investigate the expression of UPP (p97/VCP and Ub), autophagosomal (p62 and LC3) and autolysosomal proteins (Lamp1 and Lamp2) in the normal and preeclamptic human placentas and to explore the regulatory mechanism of these proteins in autophagic pathway...
July 2018: Placenta
https://www.readbyqxmd.com/read/29895095/valosin-containing-protein-vcp-p97-is-essential-for-the-intracellular-development-of-leishmania-and-its-survival-under-heat-stress
#4
Bruno Guedes Aguiar, Prasad K Padmanabhan, Carole Dumas, Barbara Papadopoulou
Valosin-containing protein (VCP)/p97/Cdc48 is one of the best-characterised type II cytosolic AAA+ ATPases most known for their role in ubiquitin-dependent protein quality control. Here, we provide functional insights into the role of the Leishmania VCP/p97 homologue (LiVCP) in the parasite intracellular development. We demonstrate that although LiVCP is an essential gene, Leishmania infantum promastigotes can grow with less VCP. In contrast, growth of axenic and intracellular amastigotes is dramatically affected upon decreased LiVCP levels in heterozygous and temperature sensitive (ts) LiVCP mutants or the expression of dominant negative mutants known to specifically target the second conserved VCP ATPase domain, a major contributor of the VCP overall ATPase activity...
June 12, 2018: Cellular Microbiology
https://www.readbyqxmd.com/read/29890203/essential-function-of-vcp-p97-in-infection-cycle-of-the-nucleopolyhedrovirus-acmnpv-in-spodoptera-frugiperda-sf9-cells
#5
Yulia V Lyupina, Pavel A Erokhov, Oksana I Kravchuk, Alexander D Finoshin, Svetlana B Abaturova, Olga V Orlova, Svetlana N Beljelarskaya, Margarita V Kostyuchenko, Victor S Mikhailov
The protein VCP/p97 (also named CDC48 and TER94) belongs to a type II subfamily of the AAA+ATPases and controls cellular proteostasis by acting upstream of proteasomes in the ubiquitin-proteasome protein degradation pathway. The function of VCP/p97 in the baculovirus infection cycle in insect cells remains unknown. Here, we identified VCP/p97 in the fall armyworm Spodoptera frugiperda (Sf9) cells and analyzed the replication of the Autographa californica multiple nucleopolyhedrovirus, AcMNPV, in Sf9 cells in which the VCP/p97 function was inhibited...
June 8, 2018: Virus Research
https://www.readbyqxmd.com/read/29719249/skeletal-muscle-specific-methyltransferase-mettl21c-trimethylates-p97-and-regulates-autophagy-associated-protein-breakdown
#6
Janica Lea Wiederstein, Hendrik Nolte, Stefan Günther, Tanja Piller, Martina Baraldo, Sawa Kostin, Wilhelm Bloch, Natalie Schindler, Marco Sandri, Bert Blaauw, Thomas Braun, Soraya Hölper, Marcus Krüger
Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSPs) that lead to muscle weakness. Here, we identify METTL21C as a skeletal muscle-specific lysine methyltransferase. Insertion of a β-galactosidase cassette into the Mettl21c mouse locus revealed that METTL21C is specifically expressed in MYH7-positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to age-dependent accumulation of autophagic vacuoles in skeletal muscle...
May 1, 2018: Cell Reports
https://www.readbyqxmd.com/read/29704548/toxicity-and-aggregation-of-the-polyglutamine-disease-protein-ataxin-3-is-regulated-by-its-binding-to-vcp-p97-in-drosophila-melanogaster
#7
Gorica Ristic, Joanna R Sutton, Kozeta Libohova, Sokol V Todi
Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat...
August 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29693262/interleukin-6-induced-overexpression-of-valosin-containing-protein-vcp-p97-is-associated-with-androgen-independent-prostate-cancer-aipc-progression
#8
Divya Duscharla, Karthik Reddy Kami Reddy, Chandrashekhar Dasari, Supriya Bhukya, Ramesh Ummanni
Though Androgen deprivation therapy (ADT) is effective initially, numerous patients become resistant to it and develop castration resistant PCa (CRPC). Cytokines promotes ligand independent activation of AR. Interleukin-6 (IL-6) levels are elevated in CRPC patients and regulate AR activity. However, progression to CRPC is not fully understood. In this study, we analyzed differential protein expression in LNCaP cells treated with IL-6 using proteomics. Results revealed altered expression of 27 proteins and Valosin-containing protein (VCP)/p97 plays a predominant role in co-regulation of altered proteins...
April 25, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29655804/characterization-of-wdr20-a-new-regulator-of-the-erad-machinery
#9
Lin-Gao Ju, Xiang Lin, Dong Yan, Qing-Lan Li, Min Wu, Lian-Yun Li
ERAD is an important process of protein quality control that eliminates misfolded or unassembled proteins from ER. Before undergoing proteasome degradation, the misfolded proteins are dislocated from ER membrane into cytosol, which requires the AAA ATPase p97/VCP and its cofactor, the NPL4-UFD1 dimer. Here, we performed a CRISPR-based screen and identify many candidates for ERAD regulation. We further confirmed four proteins, FBOX2, TRIM6, UFL1 and WDR20, are novel regulators for ERAD. Then the molecular mechanism for WDR20 in ERAD is further characterized...
July 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29599289/interaction-between-the-aaa-atpase-p97-vcp-and-a-concealed-ubx-domain-in-the-copper-transporter-atp7a-is-associated-with-motor-neuron-degeneration
#10
Ling Yi, Stephen G Kaler
The copper-transporting ATPase ATP7A contains eight transmembrane domains and is required for normal human copper homeostasis. Mutations in the ATP7A gene may lead to infantile-onset cerebral degeneration (Menkes disease); occipital horn syndrome (OHS), a related but much milder illness; or an adult-onset isolated distal motor neuropathy. The ATP7A missense mutation T994I is located in the sixth transmembrane domain of ATP7A, represents one of the variants associated with the latter phenotype, and is associated with an abnormal interaction with p97/valosin-containing protein (VCP), a hexameric AAA ATPase (ATPase associated with diverse cellular activities) with multiple biological functions...
May 18, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29599191/ap-swath-reveals-direct-involvement-of-vcp-p97-in-integrated-stress-response-signaling-through-facilitating-crep-ppp1r15b-degradation
#11
Julia Hülsmann, Bojana Kravic, Matthias Weith, Matthias Gstaiger, Ruedi H Aebersold, Ben C Collins, Hemmo Meyer
The ubiquitin-directed AAA-ATPase VCP/p97 facilitates degradation of damaged or misfolded proteins in diverse cellular stress response pathways. Resolving the complexity of its interactions with partner and substrate proteins, and understanding its links to stress signaling is therefore a major challenge. Here, we used affinity-purification SWATH mass spectrometry (AP-SWATH) to identify proteins that specifically interact with the substrate-trapping mutant, p97-E578Q. AP-SWATH identified differential interactions over a large detection range from abundant p97 cofactors to pathway-specific partners and individual ligases such as RNF185 and MUL1 that were trapped in p97-E578Q complexes...
March 29, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29521227/vcp-p97-cdc48-a-linking-of-protein-homeostasis-and-cancer-therapy
#12
B Lan, S Chai, P Wang, K Wang
VCP/p97/Cdc48, a member of the ATPases associated with diverse cellular activities (AAA) family, is necessary for the endoplasmic-reticulum-associated protein degradation (ERAD) pathway to maintain protein homeostasis. Overwhelming proteotoxic stress drove cancer cells to enhance VCP/p97/Cdc48-associated ERAD to maintain protein homeostasis for survival, demonstrating that VCP/p97/Cdc48 expression was positively correlated with cancer prognosis. More studies revealed that targeting VCP/p97/Cdc48 could be a potential target in cancer therapy...
2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/29359838/discrimination-between-the-endoplasmic-reticulum-and-mitochondria-by-spontaneously-inserting-tail-anchored-proteins
#13
Bruna Figueiredo Costa, Patrizia Cassella, Sara F Colombo, Nica Borgese
Tail-anchored (TA) proteins insert into their target organelles by incompletely elucidated posttranslational pathways. Some TA proteins spontaneously insert into protein-free liposomes, yet target a specific organelle in vivo. Two spontaneously inserting cytochrome b5 forms, b5-ER and b5-RR, which differ only in the charge of the C-terminal region, target the endoplasmic reticulum (ER) or the mitochondrial outer membrane (MOM), respectively. To bridge the gap between the cell-free and in cellula results, we analyzed targeting in digitonin-permeabilized adherent HeLa cells...
March 2018: Traffic
https://www.readbyqxmd.com/read/29320735/rybp-is-a-k63-ubiquitin-chain-binding-protein-that-inhibits-homologous-recombination-repair
#14
Mohammad A M Ali, Hilmar Strickfaden, Brian L Lee, Leo Spyracopoulos, Michael J Hendzel
Ring1-YY1-binding protein (RYBP) is a member of the non-canonical polycomb repressive complex 1 (PRC1), and like other PRC1 members, it is best described as a transcriptional regulator. However, several PRC1 members were recently shown to function in DNA repair. Here, we report that RYBP preferentially binds K63-ubiquitin chains via its Npl4 zinc finger (NZF) domain. Since K63-linked ubiquitin chains are assembled at DNA double-strand breaks (DSBs), we examined the contribution of RYBP to DSB repair. Surprisingly, we find that RYBP is K48 polyubiquitylated by RNF8 and rapidly removed from chromatin upon DNA damage by the VCP/p97 segregase...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29238611/structural-basis-for-nucleotide-modulated-p97-association-with-the-er-membrane
#15
Wai Kwan Tang, Ting Zhang, Yihong Ye, Di Xia
Association of the cytosolic AAA (ATPases associated with various cellular activities) protein p97 to membranes is essential for various cellular processes including endoplasmic reticulum (ER)-associated degradation. The p97 consists of two ATPase domains and an N domain that interacts with numerous cofactors. The N domain of p97 is known to undergo a large nucleotide-dependent conformation switch, but its physiological relevance is unclear. Here we show p97 is recruited to canine ER membranes predominantly by interacting with VCP-interacting membrane protein (VIMP), an ER-resident protein...
2017: Cell Discovery
https://www.readbyqxmd.com/read/29211715/alcohol-abuse-drug-disulfiram-targets-cancer-via-p97-segregase-adaptor-npl4
#16
Zdenek Skrott, Martin Mistrik, Klaus Kaae Andersen, Søren Friis, Dusana Majera, Jan Gursky, Tomas Ozdian, Jirina Bartkova, Zsofia Turi, Pavel Moudry, Marianne Kraus, Martina Michalova, Jana Vaclavkova, Petr Dzubak, Ivo Vrobel, Pavla Pouckova, Jindrich Sedlacek, Andrea Miklovicova, Anne Kutt, Jing Li, Jana Mattova, Christoph Driessen, Q Ping Dou, Jørgen Olsen, Marian Hajduch, Boris Cvek, Raymond J Deshaies, Jiri Bartek
Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis...
December 14, 2017: Nature
https://www.readbyqxmd.com/read/29153394/vcp-p97-mediated-unfolding-as-a-principle-in-protein-homeostasis-and-signaling
#17
REVIEW
Johannes van den Boom, Hemmo Meyer
The AAA+-type ATPase p97 governs an ever-expanding number of cellular processes reaching from degradation of damaged proteins and organelles to key signaling events and chromatin regulation with thousands of client proteins. With its relevance for cellular homeostasis and genome stability, it is linked to muscular and neuronal degeneration and, conversely, constitutes an attractive anti-cancer drug target. Its molecular function is ATP-driven protein unfolding, which is directed by ubiquitin and assisted by a host of cofactor proteins...
January 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/28949448/vcp-inhibitors-induce-endoplasmic-reticulum-stress-cause%C3%A2-cell-cycle-arrest-trigger-caspase-mediated-cell-death%C3%A2-and-synergistically-kill-ovarian-cancer-cells-in-combination-with-salubrinal
#18
(no author information available yet)
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis...
December 2016: Molecular Oncology
https://www.readbyqxmd.com/read/28939772/interaction-between-the-aaa-atpase-p97-and-its-cofactor-ataxin3-in-health-and-disease-nucleotide-induced-conformational-changes-regulate-cofactor-binding
#19
Maya V Rao, Dewight R Williams, Simon Cocklin, Patrick J Loll
p97 is an essential ATPase associated with various cellular activities (AAA+ ) that functions as a segregase in diverse cellular processes, including the maintenance of proteostasis. p97 interacts with different cofactors that target it to distinct pathways; an important example is the deubiquitinase ataxin3, which collaborates with p97 in endoplasmic reticulum-associated degradation. However, the molecular details of this interaction have been unclear. Here, we characterized the binding of ataxin3 to p97, showing that ataxin3 binds with low-micromolar affinity to both wild-type p97 and mutants linked to degenerative disorders known as multisystem proteinopathy 1 (MSP1); we further showed that the stoichiometry of binding is one ataxin3 molecule per p97 hexamer...
November 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28815021/toward-an-understanding-of-the-cdc48-p97-atpase
#20
REVIEW
Nicholas Bodnar, Tom Rapoport
A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. For example, in endoplasmic reticulum (ER)-associated protein degradation (ERAD), Cdc48/p97 pulls polyubiquitinated, misfolded proteins out of the ER and transfers them to the proteasome. Cdc48/p97 consists of an N-terminal domain and two ATPase domains (D1 and D2). Six Cdc48 monomers form a double-ring structure surrounding a central pore...
2017: F1000Research
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