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ER associated degradation

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https://www.readbyqxmd.com/read/29457782/hypothalamic-er-associated-degradation-regulates-pomc-maturation-feeding-and-age-associated-obesity
#1
Geun Hyang Kim, Guojun Shi, Diane Rm Somlo, Leena Haataja, Soobin Song, Qiaoming Long, Eduardo A Nillni, Malcolm J Low, Peter Arvan, Martin G Myers, Ling Qi
Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism...
February 19, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29452565/serum-vitamin-c-levels-modulate-the-lifespan-and-endoplasmic-reticulum-stress-response-pathways-in-mice-synthesizing-a-nonfunctional-mutant-wrn-protein
#2
Lucie Aumailley, Marie Julie Dubois, Tracy A Brennan, Chantal Garand, Eric R Paquet, Robert J Pignolo, André Marette, Michel Lebel
Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase (WRN). Mice lacking part of the helicase domain of the WRN ortholog exhibit several phenotypic features of WS. In this study, we generated a Wrn mutant line that, like humans, relies entirely on dietary sources of vitamin C (ascorbate) to survive, by crossing them to mice that lack the gulonolactone oxidase enzyme required for ascorbate synthesis. In the presence of 0.01% ascorbate (w/v) in drinking water, double-mutant mice exhibited a severe reduction in lifespan, small size, sterility, osteopenia, and metabolic profiles different from wild-type (WT) mice...
February 8, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29444958/cdc48-and-ubiquilins-confer-selective-anterograde-protein-sorting-and-entry-into-the-multivesicular-body-in-yeast
#3
Rachel Kama, Galina Gabriely, Vydehi Kanneganti, Jeffrey E Gerst
Cdc48/p97 is known primarily for the retro-translocation of misfolded proteins in ER-associated protein degradation (ERAD). Here, we uncover a novel function for both Cdc48 and the conserved UBA-UBL ubiquitin receptor (ubiquilin) proteins in yeast ( e.g. Ddi1, Dsk2, Rad23), which deliver ubiquitinated proteins to the proteasome for degradation. We show that Cdc48, its core adaptors Npl4 and Ufd1, and the ubiquilins confer the constitutive anterograde delivery of carboxypeptidase S (Cps1), a membranal hydrolase, to the multivesicular body (MVB) and vacuolar lumen...
February 14, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29443383/a-b3galt6-variant-in-patient-originally-described-as-al-gazali-syndrome-and-implicating-the-er-quality-control-in-the-mechanism-of-some-%C3%AE-3galt6-pathy-mutations
#4
A Ben-Mahmoud, S Ben-Salem, M Al-Sorkhy, A John, B R Ali, L Al-Gazali
Al-Gazali syndrome encompasses several clinical features including prenatal growth retardation, large joints contractures with camptodactyly, bilateral talipes equinovarus, small mouth, anterior segment anomalies of the eyes, and early lethality. Recently, a baby with features very similar to Al-Gazali syndrome was found to have compound heterozygous variants in B3GALT6. This gene encodes Beta-1,3-galactosyltransferase 6 (β3GalT6), an essential component of the glycosaminoglycan synthesis pathway. Pathogenic variants in B3GALT6 have also been shown to cause Ehlers-Danlos syndrome spondylodysplastic type (spEDS-B3GALT6) and spondylo-epimetaphyseal dysplasia with joint laxity type I (SEMD-JL1)...
February 14, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29433542/smurf1-facilitates-estrogen-receptor-%C3%A9-signaling-in-breast-cancer-cells
#5
Huijie Yang, Na Yu, Juntao Xu, Xiaosheng Ding, Wei Deng, Guojin Wu, Xin Li, Yingxiang Hou, Zhenhua Liu, Yan Zhao, Min Xue, Sifan Yu, Beibei Wang, Xiumin Li, Gang Niu, Hui Wang, Jian Zhu, Ting Zhuang
BACKGROUND: Estrogen receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. ER alpha positive breast cancer can be well controlled by ER alpha modulators, such as tamoxifen. However, tamoxifen resistance is commonly observed by altered ER alpha signaling. Thus, further understanding of the molecular mechanisms, which regulates ER alpha signaling, is important to improve breast cancer therapy. METHODS: SMURF1 and ER alpha protein expression levels were measured by western blot, while the ER alpha target genes were measured by real-time PCR...
February 12, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29415493/interplay-between-p-glycoprotein-expression-and-resistance-to-endoplasmic-reticulum-stressors
#6
REVIEW
Milan Hano, Lenka Tomášová, Mário Šereš, Lucia Pavlíková, Albert Breier, Zdena Sulová
Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)-a drug efflux pump (ABCB1 member of the ABC transporter gene family)-is frequently observed to be a molecular cause of MDR. The drug-efflux activity of P-gp is considered as the underlying mechanism of drug resistance against P-gp substrates and results in failure of cancer chemotherapy. Several pathological impulses such as shortages of oxygen and glucose supply, alterations of calcium storage mechanisms and/or processes of protein N-glycosylation in the endoplasmic reticulum (ER) leads to ER stress (ERS), characterized by elevation of unfolded protein cell content and activation of the unfolded protein response (UPR)...
February 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29413844/ripk3-regulates-cardiac-microvascular-reperfusion-injury-the-role-of-ip3r-dependent-calcium-overload-xo-mediated-oxidative-stress-and-f-action-filopodia-based-cellular-migration
#7
Hao Zhou, Jin Wang, Pingjun Zhu, Shunying Hu, Jun Ren
Ripk3-mediated cellular apoptosis is a major contributor to the pathogenesis of myocardial ischemia reperfusion (IR) injury. However, the mechanisms by which Ripk3 influences microvascular homeostasis and endothelial apoptosis are not completely understood. In this study, loss of Ripk3 inhibited endothelial apoptosis, alleviated luminal swelling, maintained microvasculature patency, reduced the expression of adhesion molecules and limited the myocardial inflammatory response. In vitro, Ripk3 deficiency protected endothelial cells from apoptosis and migratory arrest induced by HR injury...
January 27, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29404458/interferon-alpha-induced-hepatitis-c-virus-clearance-restores-p53-tumor-suppressor-more-than-direct-acting-antivirals
#8
Yucel Aydin, Animesh Chatterjee, Partha K Chandra, Srinivas Chava, Weina Chen, Anamika Tandon, Asha Dash, Milad Chedid, Martin W Moehlen, Frederic Regenstein, Luis A Balart, Ari Cohen, Hua Lu, Tong Wu, Srikanta Dash
The mechanism why hepatitis C virus (HCV) clearance by direct-acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)-stress response. In this study, we examined whether HCV clearance by interferon-alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes...
May 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29402832/the-cftr-associated-ligand-arrests-the-trafficking-of-the-mutant-%C3%AE-f508-cftr-channel-in-the-er-contributing-to-cystic-fibrosis
#9
Emily Bergbower, Clement Boinot, Inna Sabirzhanova, William Guggino, Liudmila Cebotaru
BACKGROUND/AIMS: The CFTR-Associated Ligand (CAL), a PDZ domain containing protein with two coiled-coil domains, reduces cell surface WT CFTR through degradation in the lysosome by a well-characterized mechanism. However, CAL's regulatory effect on ΔF508 CFTR has remained almost entirely uninvestigated. METHODS: In this study, we describe a previously unknown pathway for CAL by which it regulates the membrane expression of ΔF508 CFTR through arrest of ΔF508 CFTR trafficking in the endoplasmic reticulum (ER) using a combination of cell biology, biochemistry and electrophysiology...
January 29, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29396984/the-glycan-dependent-erad-machinery-degrades-topologically-diverse-misfolded-proteins
#10
Yun-Ji Shin, Ulrike Vavra, Christiane Veit, Richard Strasser
A great number of soluble and integral membrane proteins fold in the endoplasmic reticulum (ER) with the help of chaperones and folding factors. Despite these efforts, protein folding is intrinsically error prone and amino acid changes, alterations in posttranslational modifications or cellular stress can cause protein misfolding. Folding-defective non-native proteins are cleared from the ER and typically undergo ER-associated degradation (ERAD). Here, we investigated whether different misfolded glycoproteins require the same set of ERAD factors and are directed to HRD1 complex-mediated degradation in plants...
February 3, 2018: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/29394096/protein-quality-control-of-the-endoplasmic-reticulum-and-ubiquitin-proteasome-triggered-degradation-of-aberrant-proteins-yeast-pioneers-the-path
#11
Nicole Berner, Karl-Richard Reutter, Dieter H Wolf
Cells must constantly monitor the integrity of their macromolecular constituents. Proteins are the most versatile class of macromolecules but are sensitive to structural alterations. Misfolded or otherwise aberrant protein structures lead to dysfunction and finally aggregation. Their presence is linked to aging and a plethora of severe human diseases. Thus, misfolded proteins have to be rapidly eliminated. Secretory proteins constitute more than one-third of the eukaryotic proteome. They are imported into the endoplasmic reticulum (ER), where they are folded and modified...
February 2, 2018: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/29386036/a-novel-role-of-er-stress-signal-transducer-atf6-in-regulating-enterovirus-a71-viral-protein-stability
#12
Jia-Rong Jheng, Kean-Seng Lau, Yueh-Wen Lan, Jim-Tong Horng
BACKGROUND: Due to limited coding capacity of viral genome, enterovirus A71 (EV-A71) co-opts host nuclear proteins for its replication. Upon ER stress, the ER-localized 90 kDa activating transcription factor 6 (p90ATF6) is proteolytically cleaved to produce the transcriptionally active amino-terminal 50 kDa (p50ATF6) product where it enters the nucleus to activate a subset of unfolded protein response and ER-associated degradation (also known as ERAD) genes. During EV-A71 infection, however, this p50ATF6 product was not detected in the nucleus, and its downstream target genes were not activated...
January 31, 2018: Journal of Biomedical Science
https://www.readbyqxmd.com/read/29378775/erad-dependent-control-of-the-wnt-secretory-factor-evi
#13
Kathrin Glaeser, Manuela Urban, Emma Fenech, Oksana Voloshanenko, Dominique Kranz, Federica Lari, John C Christianson, Michael Boutros
Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β-catenin by the ubiquitin-proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)-associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP-dependent manner...
January 29, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29377281/er-stress-mediated-regulation-of-mir23a-confer-hela-cells-better-adaptability-to-utilize-glycolytic-pathway
#14
P Aswini, R Grace Raji, K Haritha, E Lincy, V B Sameer Kumar
Cancer cells exhibit increased dependency on aerobic glycolysis, a phenomenon referred as the 'Warburg effect' and therefore, blocking glycolysis by using non-metabolizable analogues of glucose, like 2-Deoxy glucose (2-DG), has been proposed to be of huge therapeutic importance. One of the major drawbacks of using 2-DG as a chemotherapeutic agent is that it can induce ER stress. ER stress is a hall mark in many solid tumors and the unfolded protein response (UPR) associated with it initiates many survival mechanisms in cancer cells...
January 29, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29374057/ring-finger-protein-145-rnf145-is-a-ubiquitin-ligase-for-sterol-induced-degradation-of-hmg-coa-reductase
#15
Lu-Yi Jiang, Wei Jiang, Na Tian, Yan-Ni Xiong, Jie Liu, Jian Wei, Kai-Yue Wu, Jie Luo, Xiong-Jie Shi, Bao-Liang Song
Cholesterol biosynthesis is tightly regulated in the cell. For example, high sterol concentrations can stimulate the degradation of the rate-limiting cholesterol biosynthesis enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCR). HMGCR is broken down by endoplasmic reticulum (ER) membrane-associated protein complexes consisting of insulin-induced genes (Insigs) and the E3 ubiquitin ligase gp78. Here, we found that HMGCR degradation is partially blunted in Chinese hamster ovary (CHO) cells lacking gp78 (gp78-KO)...
January 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29371607/degradation-routes-of-trafficking-defective-vldlr-mutants-associated-with-dysequilibrium-syndrome
#16
Praseetha Kizhakkedath, Anne John, Lihadh Al-Gazali, Bassam R Ali
Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium syndrome (DES), disrupt ligand-binding, due to endoplasmic reticulum (ER) retention of the mutants. We explored the degradation routes of these VLDLR mutants in cultured cells. Our results indicate that VLDLR mutants are retained in the ER for prolonged periods which could be facilitated by association with the ER-resident chaperone calnexin...
January 25, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29370161/crl4-antagonizes-scffbxo7-mediated-turnover-of-cereblon-and-bk-channel-to-regulate-learning-and-memory
#17
Tianyu Song, Shenghui Liang, Jiye Liu, Tingyue Zhang, Yifei Yin, Chenlu Geng, Shaobing Gao, Yan Feng, Hao Xu, Dongqing Guo, Amanda Roberts, Yuchun Gu, Yong Cang
Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBN mutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7 ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity...
January 25, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29363524/acquired-resistance-of-er-positive-breast-cancer-to-endocrine-treatment-confers-an-adaptive-sensitivity-to-trail-through-post-translational-downregulation-of-c-flip
#18
Luke Piggott, Andreia M da Silva, Timothy Robinson, Angélica Santiago-Gómez, Bruno M Simões, Michael Becker, Iduna Fichtner, Ladislav Andera, Marco Piva, Maria dM Vivanco, Christine Morris, Fouad S Alchami, Philippa Young, Peter J Barrett-Lee, Robert B Clarke, Julia Mw Gee, Richard Clarkson
PURPOSE: One-third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need.  Here we identify a specific post-translational modification that occurs during endocrine resistance and which results in tumour susceptibility to the apoptosis inducer TNF-Related Apoptosis-Inducing Ligand (TRAIL). This potentially offers a novel stratified approach to targeting endocrine resistant breast cancer...
January 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29355480/sorting-of-a-multi-subunit-ubiquitin-ligase-complex-in-the-endolysosome-system
#19
Xi Yang, Felichi Mae Arines, Weichao Zhang, Ming Li
The yeast Dsc E3 ligase complex has long been recognized as a Golgi-specific protein ubquitination system. It shares a striking sequence similarity to the Hrd1 complex that plays critical roles in the ER-associated degradation pathway. Using biochemical purification and mass spectrometry, we identified two novel Dsc subunits, which we named as Gld1 and Vld1. Surprisingly, Gld1 and Vld1 do not coexist in the same complex. Instead, they compete with each other to form two functionally independent Dsc subcomplexes...
January 22, 2018: ELife
https://www.readbyqxmd.com/read/29353883/growth-arrest-and-apoptosis-induction-in-androgen-receptor-positive-human-breast-cancer-cells-by-inhibition-of-usp14-mediated-androgen-receptor-deubiquitination
#20
Yuning Liao, Xiaohong Xia, Ningning Liu, Jianyu Cai, Zhiqiang Guo, Yanling Li, Lili Jiang, Q Ping Dou, Daolin Tang, Hongbiao Huang, Jinbao Liu
It has been well known that androgen receptor (AR) is critical to prostate cancer development and progression. It has also been documented that AR is expressed in more than 60% of breast tumors, which promotes the growth of estrogen receptor-negative (ER-)/AR-positive (AR+) breast cancer cells. Thus, AR might be a potential therapeutic target for AR-positive/ER-negative breast cancer patients. Previously we reported that in prostate cancer cells proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14) stabilized AR protein level by removing its ubiquitin chain...
January 22, 2018: Oncogene
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