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19S regulatory particle

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https://www.readbyqxmd.com/read/29556699/the-novel-deubiquitinase-inhibitor-b-ap15-induces-direct-and-nk-cell-mediated-antitumor-effects-in-human-mantle-cell-lymphoma
#1
Korbinian N Kropp, Stefanie Maurer, Kathrin Rothfelder, Bastian J Schmied, Kim L Clar, Moritz Schmidt, Benedikt Strunz, Hans-Georg Kopp, Alexander Steinle, Frank Grünebach, Susanne M Rittig, Helmut R Salih, Daniela Dörfel
The first therapeutic proteasome inhibitor bortezomib has clinical efficacy in mantle cell lymphoma (MCL) which resulted in its incorporation in treatment algorithms for this disease. Impairment of proteasomal function by bortezomib is mediated via inhibition of the 20S core particle. However, proteasome function can also be modified by targeting upstream components of the ubiquitin-proteasome system. Recently, b-AP15 has been identified as a small molecule achieving proteasome inhibition by targeting the deubiquitinase (DUB) activity of the 19S regulatory subunit and was found to inhibit cancer cell growth in preclinical analyses...
March 19, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29545515/a-common-mechanism-of-proteasome-impairment-by-neurodegenerative-disease-associated-oligomers
#2
Tiffany A Thibaudeau, Raymond T Anderson, David M Smith
Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin-proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer's, Parkinson's, and Huntington's disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates...
March 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29507114/hsp70-hsp110-chaperones-deliver-ubiquitin-dependent-and-independent-substrates-to-the-26s-proteasome-for-proteolysis
#3
Ganapathi Kandasamy, Claes Andréasson
In protein quality control, proteotoxic misfolded proteins are recognized by molecular chaperones, ubiquitylated by dedicated quality-control ligases and delivered to 26S proteasome for degradation. The chaperone Hsp70 and its nucleotide exchange factor Hsp110 functions in the degradation of misfolded proteins by the ubiquitin-proteasome system via poorly understood mechanisms. Here we report that yeast Hsp110 (Sse1 and Sse2) functions in the degradation of Hsp70-associated ubiquitin conjugates at the post-ubiquitylation step and is required for the proteasomal degradation of ubiquitin-independent substrates...
March 5, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29435775/quercetin-prevents-in-vivo-and-in-vitro-myocardial-hypertrophy-through-the-proteasome-gsk-3-pathway
#4
Kuixiang Chen, Mubarak Rekep, Wei Wei, Qian Wu, Qin Xue, Sujuan Li, Jiahui Tian, Quan Yi, Genshui Zhang, Guiping Zhang, Qing Xiao, Jiandong Luo, Yinghua Liu
PURPOSE: Quercetin, a flavonoid, has been reported to ameliorate cardiovascular diseases, such as cardiac hypertrophy. However, the mechanism is not completely understood. In this study, a mechanism related to proteasome-glycogen synthesis kinase 3 (GSK-3) was elucidated in rats and primary neonatal cardiomyocytes. METHODS: Rats were subjected to sham or constriction of abdominal aorta surgery groups and treated with or without quercetin for 8 weeks. Angiotensin II (Ang II)-induced primary cardiomyocytes were cultured with quercetin treatment or not for 48 h...
February 12, 2018: Cardiovascular Drugs and Therapy
https://www.readbyqxmd.com/read/29401458/sem1-links-proteasome-stability-and-specificity-to-multicellular-development
#5
Miriam Kolog Gulko, Gabriele Heinrich, Carina Gross, Blagovesta Popova, Oliver Valerius, Piotr Neumann, Ralf Ficner, Gerhard H Braus
The transition from vegetative growth to multicellular development represents an evolutionary hallmark linked to an oxidative stress signal and controlled protein degradation. We identified the Sem1 proteasome subunit, which connects stress response and cellular differentiation. The sem1 gene encodes the fungal counterpart of the human Sem1 proteasome lid subunit and is essential for fungal cell differentiation and development. A sem1 deletion strain of the filamentous fungus Aspergillus nidulans is able to grow vegetatively and expresses an elevated degree of 20S proteasomes with multiplied ATP-independent catalytic activity compared to wildtype...
February 5, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29376192/modifications-of-the-26s-proteasome-during-boar-sperm-capacitation
#6
Michal Zigo, Karl Kerns, Miriam Sutovsky, Peter Sutovsky
Protein ubiquitination is a stable, reversible post-translational modification, targeting proteins for degradation/recycling by the 26S proteasome in a well-characterized enzymatic cascade. Studies have revealed the role of UPS in the regulation of fertilization, including sperm-zona pellucida interactions and the early event of sperm capacitation. The present study investigates the changes in proteasome compartmentalization, subunit composition and post-translational modifications during in vitro capacitation of fresh boar spermatozoa...
January 29, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29141908/two-distinct-regulatory-mechanisms-of-transcriptional-initiation-in-response-to-nutrient-signaling
#7
Jannatul Ferdoush, Rwik Sen, Amala Kaja, Priyanka Barman, Sukesh R Bhaumik
SAGA (Spt-Ada-Gcn5-Acetyltransferase) and TFIID (transcription factor IID) have been previously shown to facilitate the formation of the PIC (pre-initiation complex) at the promoters of two distinct sets of genes. Here, we demonstrate that TFIID and SAGA differentially participate in the stimulation of PIC formation (and hence transcriptional initiation) at the promoter of PHO84 , a gene for the high-affinity inorganic phosphate (Pi ) transporter for crucial cellular functions, in response to nutrient signaling...
January 2018: Genetics
https://www.readbyqxmd.com/read/28968984/a-novel-deubiquitinase-inhibitor-b-ap15-triggers-apoptosis-in-both-androgen-receptor-dependent-and-independent-prostate-cancers
#8
Jianyu Cai, Xiaohong Xia, Yuning Liao, Ningning Liu, Zhiqiang Guo, Jinghong Chen, Li Yang, Huidan Long, Qianqian Yang, Xiaolan Zhang, Lu Xiao, Xuejun Wang, Hongbiao Huang, Jinbao Liu
Prostate cancer (PCa) remains a leading cause of cancer-related death in men. Especially, a subset of patients will eventually progress to the metastatic castrate-resistant prostate cancer (CRPC) which is currently incurable. Deubiquitinases (DUBs) associated with the 19S proteasome regulatory particle are increasingly emerging as significant therapeutic targets in numerous cancers. Recently, a novel small molecule b-AP15 is identified as an inhibitor of the USP14/UCHL5 (DUBs) of the 19S proteasome, resulting in cell growth inhibition and apoptosis in several human cancer cell lines...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28821611/the-proteasome-interacting-ecm29-protein-disassembles-the-26s-proteasome-in-response-to-oxidative-stress
#9
Xiaorong Wang, Ilan E Chemmama, Clinton Yu, Alexander Huszagh, Yue Xu, Rosa Viner, Sarah A Block, Peter Cimermancic, Scott D Rychnovsky, Yihong Ye, Andrej Sali, Lan Huang
Oxidative stress has been implicated in multiple human neurological and other disorders. Proteasomes are multi-subunit proteases critical for the removal of oxidatively damaged proteins. To understand stress-associated human pathologies, it is important to uncover the molecular events underlying the regulation of proteasomes upon oxidative stress. To this end, we investigated H2 O2 stress-induced molecular changes of the human 26S proteasome and determined that stress-induced 26S proteasome disassembly is conserved from yeast to human...
September 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28767417/a-novel-deubiquitinase-inhibitor-b-ap15-triggers-apoptosis-in-both-androgen-receptor-dependent-and-independent-prostate-cancers
#10
Jianyu Cai, Xiaohong Xia, Yuning Liao, Ningning Liu, Zhiqiang Guo, Jinghong Chen, Li Yang, Huidan Long, Qianqian Yang, Xiaolan Zhang, Lu Xiao, Xuejun Wang, Hongbiao Huang, Jinbao Liu
Prostate cancer (PCa) remains a leading cause of cancer-related death in men. Especially, a subset of patients will eventually progress to the metastatic castrate-resistant prostate cancer (CRPC) which is currently incurable. Deubiquitinases (DUBs) associated with the 19S proteasome regulatory particle are increasingly emerging as significant therapeutic targets in numerous cancers. Recently, a novel small molecule b-AP15 is identified as an inhibitor of the USP14/UCHL5 (DUBs) of the 19S proteasome, resulting in cell growth inhibition and apoptosis in several human cancer cell lines...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28662109/phosphorylation-of-the-19s-regulatory-particle-atpase-subunit-rpt6-modifies-susceptibility-to-proteotoxic-stress-and-protein-aggregation
#11
Esther Magdalena Marquez-Lona, Ana Lilia Torres-Machorro, Frankie R Gonzales, Lorraine Pillus, Gentry N Patrick
The ubiquitin proteasome system (UPS) is a highly conserved and tightly regulated biochemical pathway that degrades the majority of proteins in eukaryotic cells. Importantly, the UPS is responsible for counteracting altered protein homeostasis induced by a variety of proteotoxic stresses. We previously reported that Rpt6, the ATPase subunit of the 19S regulatory particle (RP) of the 26S proteasome, is phosphorylated in mammalian neurons at serine 120 in response to neuronal activity. Furthermore, we found that Rpt6 S120 phosphorylation, which regulates the activity and distribution of proteasomes in neurons, is relevant for proteasome-dependent synaptic remodeling and function...
2017: PloS One
https://www.readbyqxmd.com/read/28583440/proteasome-structure-and-assembly
#12
REVIEW
Lauren Budenholzer, Chin Leng Cheng, Yanjie Li, Mark Hochstrasser
The eukaryotic 26S proteasome is a large multisubunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle and the 20S core particle. Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the regulatory particle is to recognize, unfold, deubiquitylate, and translocate substrates into the core particle, which contains the proteolytic sites of the proteasome...
November 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28559284/the-autism-linked-ube3a-t485a-mutant-e3-ubiquitin-ligase-activates-the-wnt-%C3%AE-catenin-pathway-by-inhibiting-the-proteasome
#13
Jason J Yi, Smita R Paranjape, Matthew P Walker, Rajarshi Choudhury, Justin M Wolter, Giulia Fragola, Michael J Emanuele, Michael B Major, Mark J Zylka
UBE3A is a HECT domain E3 ubiquitin ligase whose dysfunction is linked to autism, Angelman syndrome, and cancer. Recently, we characterized a de novo autism-linked UBE3A mutant (UBE3AT485A ) that disrupts phosphorylation control of UBE3A activity. Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A...
July 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28539385/phosphatase-ublcp1-controls-proteasome-assembly
#14
Shuangwu Sun, Sisi Liu, Zhengmao Zhang, Wang Zeng, Chuang Sun, Tao Tao, Xia Lin, Xin-Hua Feng
Ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1), an FCP/SCP phosphatase family member, was identified as the first proteasome phosphatase. UBLCP1 binds to proteasome subunit Rpn1 and dephosphorylates the proteasome in vitro However, it is still unclear which proteasome subunit(s) are the bona fide substrate(s) of UBLCP1 and the precise mechanism for proteasome regulation remains elusive. Here, we show that UBLCP1 selectively binds to the 19S regulatory particle (RP) through its interaction with Rpn1, but not the 20S core particle (CP) or the 26S proteasome holoenzyme...
May 2017: Open Biology
https://www.readbyqxmd.com/read/28476333/identification-of-4-arylidene-curcumin-analogues-as-novel-proteasome-inhibitors-for-potential-anticancer-agents-targeting-19s-regulatory-particle-associated-deubiquitinase
#15
Xin Yue, Yinglin Zuo, Hongpeng Ke, Jiaming Luo, Lanlan Lou, Wenjing Qin, Youqiao Wang, Ziyi Liu, Daoyuan Chen, Haixia Sun, Weichao Zheng, Cuige Zhu, Ruimin Wang, Gesi Wen, Jun Du, Binhua Zhou, Xianzhang Bu
The proteasomal 19S regulatory particle (RP) associated deubiquitinases (DUBs) have attracted much attention owing to their potential as a therapeutic target for cancer therapy. Identification of new entities against 19S RP associated DUBs and illustration of the underlying mechanisms is crucial for discovery of novel proteasome blockers. In this study, a series of 4-arylidene curcumin analogues were identified as potent proteasome inhibitor by preferentially blocking deubiquitinase function of proteasomal 19S RP with moderate 20S CP inhibition...
August 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28442575/structure-and-energetics-of-pairwise-interactions-between-proteasome-subunits-rpn2-rpn13-and-ubiquitin-clarify-a-substrate-recruitment-mechanism
#16
Ryan T VanderLinden, Casey W Hemmis, Tingting Yao, Howard Robinson, Christopher P Hill
The 26S proteasome is a large cellular assembly that mediates the selective degradation of proteins in the nucleus and cytosol and is an established target for anticancer therapeutics. Protein substrates are typically targeted to the proteasome through modification with a polyubiquitin chain, which can be recognized by several proteasome-associated ubiquitin receptors. One of these receptors, RPN13/ADRM1, is recruited to the proteasome through direct interaction with the large scaffolding protein RPN2 within the 19S regulatory particle...
June 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28396413/ubiquitinated-proteins-promote-the-association-of-proteasomes-with-the-deubiquitinating-enzyme-usp14-and-the-ubiquitin-ligase-ube3c
#17
Chueh-Ling Kuo, Alfred Lewis Goldberg
In mammalian cells, the 26S proteasomes vary in composition. In addition to the standard 28 subunits in the 20S core particle and 19 subunits in each 19S regulatory particle, a small fraction (about 10-20% in our preparations) also contains the deubiquitinating enzyme Usp14/Ubp6, which regulates proteasome activity, and the ubiquitin ligase, Ube3c/Hul5, which enhances proteasomal processivity. When degradation of ubiquitinated proteins in cells was inhibited, levels of Usp14 and Ube3c on proteasomes increased within minutes...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28322792/molecular-chaperones-of-the-hsp70-family-assist-in-the-assembly-of-20s-proteasomes
#18
Lindsay J Hammack, Kyle Firestone, William Chang, Andrew R Kusmierczyk
The eukaryotic 26S proteasome is a large protease comprised of two major sub assemblies, the 20S proteasome, or core particle (CP), and the 19S regulatory particle (RP). Assembly of the CP and RP is assisted by an expanding list of dedicated assembly factors. For the CP, this includes Ump1 and the heterodimeric Pba1-Pba2 and Pba3-Pba4 proteins. It is not known how many additional proteins that assist in proteasome biogenesis remain to be discovered. Here, we demonstrate that two members of the Hsp70 family in yeast, Ssa1 and Ssa2, play a direct role in CP assembly...
April 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27932072/a-case-for-sec61-channel-involvement-in-erad
#19
REVIEW
Karin Römisch
Proteins that misfold in the endoplasmic reticulum (ER) need to be transported back to the cytosol for degradation by proteasomes, a process known as ER-associated degradation (ERAD). The first candidate discussed as a retrograde protein transport conduit was the Sec61 channel which is responsible for secretory protein transport into the ER during biogenesis. The Sec61 channel binds the proteasome 19S regulatory particle which can extract an ERAD substrate from the ER. Nevertheless its role as a general export channel has been dismissed, and Hrd1 and Der1 have been proposed as alternatives...
March 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/27648923/human-telomerase-reverse-transcriptase-htert-positively-regulates-26s-proteasome-activity
#20
Eunju Im, Jong Bok Yoon, Han-Woong Lee, Kwang Chul Chung
Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, an RNA-dependent DNA polymerase that elongates telomeric DNA. hTERT displays several extra-telomeric functions that are independent of its telomere-regulatory function, including tumor progression, and neuronal cell death regulation. In this study, we evaluated these additional hTERT non-telomeric functions. We determined that hTERT interacts with several 19S and 20S proteasome subunits. The 19S regulatory particle and 20S core particle are part of 26S proteasome complex, which plays a central role in ubiquitin-dependent proteolysis...
August 2017: Journal of Cellular Physiology
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