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ER associated degradation

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https://www.readbyqxmd.com/read/27932072/a-case-for-sec61-channel-involvement-in-erad
#1
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...
December 5, 2016: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/27928013/herpes-simplex-virus-1-ul41-protein-suppresses-the-ire1-xbp1-signal-pathway-of-the-unfolded-protein-response-via-its-rnase-activity
#2
Pengchao Zhang, Chenhe Su, Zhangtao Jiang, Chunfu Zheng
: During viral infection, accumulation of viral proteins can cause stress in the endoplasmic reticulum (ER) and trigger the unfolded protein response (UPR) to restore the ER homeostasis. Inositol-requiring enzyme 1 (IRE1)-dependent pathway is the most conserved one of the three UPR signal pathways. Upon activation, IRE1 splices out an intron from the unspliced inactive form X-box binding protein 1 (XBP1(u)) mRNA and produces a transcriptionally potent spliced form (XBP1(s)). Previous studies have reported that the IRE1/XBP1 pathway is inhibited upon herpes simplex virus 1 (HSV-1) infection, however, the underlying molecular mechanism is still illusive...
December 7, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27922637/a-human-carboxypeptidase-e-nf-%C3%AE-1-gene-mutation-in-an-alzheimer-s-disease-patient-leads-to-dementia-and-depression-in-mice
#3
Y Cheng, N X Cawley, T Yanik, S R K Murthy, C Liu, F Kasikci, D Abebe, Y P Loh
Patients with Alzheimer's disease (AD), a common dementia among the aging population, often also suffer from depression. This comorbidity is poorly understood. Although most forms of AD are not genetically inherited, we have identified a new human mutation in the carboxypeptidase E (CPE)/neurotrophic factor-α1 (NF-α1) gene from an AD patient that caused memory deficit and depressive-like behavior in transgenic mice. This mutation consists of three adenosine inserts, introducing nine amino acids, including two glutamines into the mutant protein, herein called CPE-QQ...
December 6, 2016: Translational Psychiatry
https://www.readbyqxmd.com/read/27920251/a-homeostatic-shift-facilitates-endoplasmic-reticulum-proteostasis-through-transcriptional-integration-of-proteostatic-stress-response-pathways
#4
Liam Baird, Tadayuki Tsujita, Eri Kobayashi, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Masayuki Yamamoto
Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Whilst the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system (UPS), which functions to degrade damaged, unfolded or short half-life proteins...
December 5, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27903760/interactions-between-intersubunit-transmembrane-domains-regulate-the-chaperone-dependent-degradation-of-an-oligomeric-membrane-protein
#5
Teresa M Buck, Alexa S Jordahl, Megan E Yates, Mike Preston, Emily Cook, Thomas R Kleyman, Jeffrey L Brodsky
The Epithelial Sodium Channel (ENaC) in kidney regulates blood pressure through control of sodium and volume homeostasis, and in lung ENaC regulates the volume of airway and alveolar fluids.  ENaC is a heterotrimer of homologous α-, β-, and γ-subunits, and assembles in the Endoplasmic Reticulum (ER) before it traffics and functions at the plasma membrane. Improperly folded or orphaned ENaC subunits are subject to ER quality control and targeted for ER associated degradation (ERAD). We previously established that a conserved, ER lumenal, molecular chaperone, Lhs1/GRP170, selects αENaC, but not β- or γENaC, for degradation when the ENaC subunits were individually expressed...
November 30, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27895152/spatio-temporal-uncoupling-of-mirna-mediated-translational-repression-and-target-rna-degradation-controls-mirnp-recycling-in-mammalian-cells
#6
Mainak Bose, Bahnisikha Barman, Avijit Goswami, Suvendra N Bhattacharyya
miRNA-mediated repression control expression of more than half of protein coding genes in metazoan animals. Translation repression is associated with target mRNA degradation initiated by decapping and deadenylation of the repressed mRNAs. Earlier evidence suggest Endoplasmic Reticulum (ER) as the site where miRNPs interact with their targets before the translation repression sets in but the subcellular location of subsequent degradation of miRNA-repressed messages is largely unidentified. Here, we explore the subcellular distribution of essential components of degradation machineries of miRNA-targeted mRNAs...
November 28, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27881664/lipid-disequilibrium-disrupts-er-proteostasis-by-impairing-erad-substrate-glycan-trimming-and-dislocation
#7
Milton To, Clark W H Peterson, Melissa A Roberts, Jessica L Counihan, Tiffany T Wu, Mercedes S Forster, Daniel K Nomura, James A Olzmann
The endoplasmic reticulum (ER) mediates the folding, maturation, and deployment of the secretory proteome. Proteins that fail to achieve their native conformation are retained in the ER and targeted for clearance by ER-associated degradation (ERAD), a sophisticated process that mediates the ubiquitin-dependent delivery of substrates to the 26S proteasome for proteolysis. Recent findings indicate that inhibition of long-chain acyl-CoA synthetases with triacsin C, a fatty acid analog, impairs lipid droplet (LD) biogenesis and ERAD, suggesting a role for LDs in ERAD...
November 23, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27879270/breast-cancer-resistance-to-antiestrogens-is-enhanced-by-increased-er-degradation-and-erbb2-expression
#8
Tomohiro Shibata, Kosuke Watari, Hiroto Izumi, Akihiko Kawahara, Satoshi Hattori, Chihiro Fukumitsu, Yuichi Murakami, Ryuji Takahashi, Uhi Toh, Ken-Ichi Ito, Shigehiro Ohdo, Maki Tanaka, Masayoshi Kage, Michihiko Kuwano, Mayumi Ono
Endocrine therapies effectively improve the outcomes of patients with estrogen receptor (ER)-positive breast cancer. However, the emergence of drug-resistant tumors creates a core clinical challenge. In breast cancer cells rendered resistant to the antiestrogen fulvestrant, we defined causative mechanistic roles for the transcription factor YBX1 and the levels of ER and the ERBB2 receptor. Enforced expression of YBX1 in parental cells conferred resistance against tamoxifen and fulvestrant in vitro and in vivo...
November 22, 2016: Cancer Research
https://www.readbyqxmd.com/read/27869218/n-linked-glycosylation-at-asn152-on-cd147-affects-protein-folding-and-stability-promoting-tumour-metastasis-in-hepatocellular-carcinoma
#9
Jiang-Hua Li, Wan Huang, Peng Lin, Bo Wu, Zhi-Guang Fu, Hao-Miao Shen, Lin Jing, Zhen-Yu Liu, Yang Zhou, Yao Meng, Bao-Qing Xu, Zhi-Nan Chen, Jian-Li Jiang
Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer, is a transmembrane glycoprotein that mediates oncogenic processes partly through N-glycosylation modifications. N-glycosylation has been demonstrated to be instrumental for the regulation of CD147 function during malignant transformation. However, the role that site-specific glycosylation of CD147 plays in its defective function in hepatocellular carcinomacells needs to be determined. Here, we demonstrate that the modification of N-glycosylation at Asn152 on CD147 strongly promotes hepatocellular carcinoma (HCC) invasion and migration...
November 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27854284/the-e3-ubiquitin-ligase-tmem129-is-a-tri-spanning-transmembrane-protein
#10
Michael L van de Weijer, Guus H van Muijlwijk, Linda J Visser, Ana I Costa, Emmanuel J H J Wiertz, Robert Jan Lebbink
Misfolded proteins from the endoplasmic reticulum (ER) are transported back into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 hijacks this ER-associated protein degradation (ERAD) pathway to downregulate human leukocyte antigen (HLA) class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T-lymphocytes. Recently, we identified the E3 ubiquitin ligase transmembrane protein 129 (TMEM129) as a key player in this process, where interference with TMEM129 activity in human cells completely abrogates US11-mediated class I degradation...
November 15, 2016: Viruses
https://www.readbyqxmd.com/read/27852857/hepatitis-c-virus-induced-rab32-aggregation-and-its-implication-in-virion-assembly
#11
Tu M Pham, Si C Tran, Yun-Sook Lim, Soon B Hwang
: Hepatitis C virus (HCV) is highly dependent on cellular factors for viral propagation. Using high-throughput next-generation sequencing, we analyzed the host transcriptomic changes and identified 30 candidate genes which were up-regulated in cell culture-grown HCV (HCVcc)-infected cells. Of these candidates, we selected Rab32 for further investigation. Rab32 is a small GTPase that regulates a variety of intracellular membrane-trafficking events in various cell types. In this study, we demonstrated that both mRNA and protein levels of Rab32 were increased in HCV-infected cells...
November 16, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27845303/new-insights-into-estrogenic-regulation-of-o-6-methylguanine-dna-methyltransferase-mgmt-in-human-breast-cancer-cells-co-degradation-of-er-%C3%AE-and-mgmt-proteins-by-fulvestrant-or-o-6-benzylguanine-indicates-fresh-avenues-for-therapy
#12
Ameya Paranjpe, Nathan I Bailey, Santhi Konduri, George C Bobustuc, Francis Ali-Osman, Mohd A Yusuf, Surendra R Punganuru, Hanumantha Rao Madala, Debasish Basak, Agm Mostofa, Kalkunte S Srivenugopal
Endocrine therapy using estrogen receptor-α (ER-α) antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O(6)-methylguanine DNA methyltransferase (MGMT), a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines (MCF-7, T47D) and ER- negative cell lines (MDAMB-468, MDAMB-231), and established inhibitors of ER-α and MGMT, namely, ICI-182,780 (Faslodex) and O(6)-benzylguanine, respectively, were used to study MGMT- ER interactions...
September 2016: Journal of Biomedical Research
https://www.readbyqxmd.com/read/27827840/usp19-mediated-deubiquitination-facilitates-the-stabilization-of-hrd1-ubiquitin-ligase
#13
Kumi Harada, Masako Kato, Nobuhiro Nakamura
In the endoplasmic reticulum (ER), misfolded and unfolded proteins are eliminated by a process called ER-associated protein degradation (ERAD) in order to maintain cell homeostasis. In the ERAD pathway, several ER-localized E3 ubiquitin ligases target ERAD substrate proteins for ubiquitination and subsequent proteasomal degradation. However, little is known about how the functions of the ERAD ubiquitin ligases are regulated. Recently, USP19, an ER-anchored deubiquitinating enzyme (DUB), has been suggested to be involved in the regulation of ERAD...
November 2, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27810942/proteomes-and-ubiquitylomes-analysis-reveals-the-involvement-of-ubiquitination-in-protein-degradation
#14
Jianhang Guo, Juanxu Liu, Qian Wei, Rongmin Wang, Weiyuan Yang, Yueyue Ma, Guoju Chen, Yuyixun Yu
Petal senescence is a complex programmed process. It has been previously demonstrated that treatment with ethylene, a plant hormone involved in senescence, can extensively alter transcriptome and proteome profiles in plants. However, little is known regarding the impact of ethylene on post-translational modification (PTM) or the association between PTM and the proteome. Protein degradation is one of the hallmarks of senescence, and ubiquitination, a major PTM in eukaryotes, plays important roles in protein degradation...
November 3, 2016: Plant Physiology
https://www.readbyqxmd.com/read/27803995/quality-control-of-glycoprotein-folding-and-erad-the-role-of-n-glycan-handling-edem1-and-os-9
#15
REVIEW
Jürgen Roth, Christian Zuber
Protein N-glycosylation and quality control of protein folding as well as the connected ER-associated degradation of misfolded glycoproteins (ERAD) are not only evolutionary highly conserved but also functionally linked. It is now established that particular N-glycan structures which result from processing reactions by exo-glycosidases in the ER are of importance for glycoprotein folding and for ERAD. Thus, mono-glucosylated N-glycan intermediates harbor structural information which is important for promoting glycoprotein folding...
November 1, 2016: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/27785701/the-opposite-role-of-two-uba-ubx-containing-proteins-p47-and-saks1-in-the-degradation-of-a-single-erad-substrate-%C3%AE-tcr
#16
Eun Sil Park, Yung Joon Yoo, Muthukumar Elangovan
The UBA-UBX domain-containing proteins can interact with ubiquitinated substrates and p97 during endoplasmic reticulum-associated degradation (ERAD). Here, we found that the expressions of all UBA-UBX genes p47, SAKS1, UBXD8, FAF1, and UBXD7 were elevated upon ER stress, albeit with different levels. Of which p47, SAKS1, and UBXD8 are 'immediate' respondents whereas FAF1 and UBXD7 were 'late' respondents to ER stress. Interestingly, the expression of specific UBA-UBX genes were altered in cells stably expressing three different ERAD substrates such as α-TCR, α1-antitrypsin, and δCD3...
October 26, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27780373/p62-sqstm1-is-required-for-the-protection-against-endoplasmic-reticulum-stress-induced-apoptotic-cell-death
#17
Jeong Su Park, Sue Young Oh, Da Hyun Lee, Yu Seol Lee, Su Haeng Sung, Hye Won Ji, Moon Joo Lee, Yong-Ho Lee, Sue Goo Rhee, Soo Han Bae
Endoplasmic reticulum (ER) stress is triggered by various cellular stresses that disturb protein folding or calcium homeostasis in the ER. To cope with these stresses, ER stress activates the unfolded protein response (UPR) pathway, but unresolved ER stress induces reactive oxygen species (ROS) accumulation leading to apoptotic cell death. However, the mechanisms that underlie protection from ER stress-induced cell death are not clearly defined. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway plays a crucial role in the protection of cells against ROS-mediated oxidative damage...
November 23, 2016: Free Radical Research
https://www.readbyqxmd.com/read/27777379/impaired-autophagy-activity-is-linked-to-elevated-er-stress-and-inflammation-in-aging-adipose-tissue
#18
Amiya Kumar Ghosh, Theresa Mau, Martin O'Brien, Sanjay Garg, Raymond Yung
Adipose tissue dysfunction in aging is associated with inflammation, metabolic syndrome and other diseases. We propose that impaired protein homeostasis due to compromised lysosomal degradation (micro-autophagy) might promote aberrant ER stress response and inflammation in aging adipose tissue. Using C57BL/6 mouse model, we demonstrate that adipose tissue-derived stromal vascular fraction (SVF) cells from old (18-20 months) mice have reduced expression of autophagy markers as compared to the younger (4-6 months) cohort...
October 24, 2016: Aging
https://www.readbyqxmd.com/read/27777122/mapping-wild-type-and-r345w-fibulin-3-intracellular-interactomes
#19
John D Hulleman, Joseph C Genereux, Annie Nguyen
Fibulin-3 (F3) is an important, disulfide-rich, extracellular matrix glycoprotein that has been associated with a number of diseases ranging from cancer to retinal degeneration. An Arg345Trp (R345W) mutation in F3 causes the rare, autosomal dominant macular dystrophy, Malattia Leventinese. The purpose of this study was to identify and validate novel intracellular interacting partners of wild-type (WT) and R345W F3 in retinal pigment epithelium cells. We used stable isotope labeling by amino acids in cell culture (SILAC) to generate 'heavy' and 'light' isotopically labeled ARPE-19 cell populations which were subsequently infected with adenovirus encoding for FLAG-tagged WT or R345W F3...
October 21, 2016: Experimental Eye Research
https://www.readbyqxmd.com/read/27761161/molecular-pathogenesis-of-long-qt-syndrome-type-2
#20
Jennifer L Smith, Corey L Anderson, Don E Burgess, Claude S Elayi, Craig T January, Brian P Delisle
The molecular mechanisms underlying congenital long QT syndrome (LQTS) are now beginning to be understood. New insights into the etiology and therapeutic strategies are emerging from heterologous expression studies of LQTS-linked mutant proteins, as well as inducible pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from LQTS patients. This review focuses on the major molecular mechanism that underlies LQTS type 2 (LQT2). LQT2 is caused by loss of function (LOF) mutations in KCNH2 (also known as the human Ether-à-go-go-Related Gene or hERG)...
October 2016: Journal of Arrhythmia
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