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ER associated degradation

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https://www.readbyqxmd.com/read/29655804/characterization-of-wdr20-a-new-regulator-of-the-erad-machinery
#1
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...
April 12, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29650545/regulation-of-blood-pressure-by-targeting-ca-v-1-2-galectin-1-protein-interaction
#2
Zhenyu Hu, Guang Li, Jiong-Wei Wang, Suet Yen Chong, Dejie Yu, Xiaoyuan Wang, Jia Lin Soon, Mui Cheng Liang, Yuk Peng Wong, Na Huang, Henry M Colecraft, Ping Liao, Tuck Wah Soong
Background -L-type CaV 1.2 channels play crucial roles in regulation of blood pressure. Galectin-1 (Gal-1), has been reported to bind to the I-II loop of CaV 1.2 channels to reduce their current density. However, the mechanistic understanding for the down-regulation of CaV 1.2 channels by Gal-1, and whether Gal-1 plays a direct role in blood pressure regulation remain unclear. Methods - In vitro experiments involving co-IP, western blot, patch-clamp recordings, immunohistochemistry and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 down-regulates CaV 1...
April 12, 2018: Circulation
https://www.readbyqxmd.com/read/29628874/saha-vorinostat-corrects-inhibitory-synaptic-deficits-caused-by-missense-epilepsy-mutations-to-the-gaba-a-receptor-%C3%AE-2-subunit
#3
Nela Durisic, Angelo Keramidas, Christine L Dixon, Joseph W Lynch
The GABAA receptor (GABAA R) α1 subunit A295D epilepsy mutation reduces the surface expression of α1A295D β2γ2 GABAA Rs via ER-associated protein degradation. Suberanilohydroxamic acid (SAHA, also known as Vorinostat) was recently shown to correct the misfolding of α1A295D subunits and thereby enhance the functional surface expression of α1A295D β2γ2 GABAA Rs. Here we investigated whether SAHA can also restore the surface expression of γ2 GABAA R subunits that incorporate epilepsy mutations (N40S, R43Q, P44S, R138G) known to reduce surface expression via ER-associated protein degradation...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29627384/can-modulators-of-apolipoproteinb-biogenesis-serve-as-an-alternate-target-for-cholesterol-lowering-drugs
#4
REVIEW
Lynley M Doonan, Edward A Fisher, Jeffrey L Brodsky
Understanding the molecular defects underlying cardiovascular disease is necessary for the development of therapeutics. The most common method to lower circulating lipids, which reduces the incidence of cardiovascular disease, is statins, but other drugs are now entering the clinic, some of which have been approved. Nevertheless, patients cannot tolerate some of these therapeutics, the drugs are costly, or the treatments are approved for only rare forms of disease. Efforts to find alternative treatments have focused on other factors, such as apolipoproteinB (apoB), which transports cholesterol in the blood stream...
April 5, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29616874/porphyromonas-gingivalis-traffics-into-endoplasmic-reticulum-rich-autophagosomes-for-successful-survival-in-human-gingival-epithelial-cells
#5
Kyulim Lee, JoAnn S Roberts, Chul Hee Choi, Kalina R Atanasova, Özlem Yilmaz
Porphyromonas gingivalis, an opportunistic pathogen usurps gingival epithelial cells (GECs) as primary intracellular niche for its colonization in the oral mucosa. However, the precise characterization of the intracellular trafficking and fate of P. gingivalis in GECs remains incomplete. Therefore, we employed high-resolution three-dimensional-transmission-electron-microscopy to determine the subcellular location of P. gingivalis in human primary GECs upon invasion. Serial sections of infected-GECs and their tomographic reconstruction depicted ER-rich-double-membrane autophagosomal-vacuoles harboring P...
April 4, 2018: Virulence
https://www.readbyqxmd.com/read/29594345/ubc7-ube2g2-ortholog-in-entamoeba-histolytica-connection-with-the-plasma-membrane-and-phagocytosis
#6
Rinki Kumari, Preeti Gupta, Swati Tiwari
Endoplasmic reticulum (ER)-associated degradation (ERAD) and unfolded protein response (UPR) pathways are important for quality and quantity control of membrane and secretory proteins. We have identified orthologs of ER-associated ubiquitin conjugating enzymes (E2s) Ubc6/Ube2j2 and Ubc7/Ube2g2, ubiquitin ligases (E3) Hrd1 and GP78/AMFR, and sensor of UPR, Ire1 in E. histolytica that show conservation of important features of these proteins. Biochemical characterization of the ortholog of ERAD E2, Ubc7/Ube2g2 (termed as EhUbc7), was carried out...
March 28, 2018: Parasitology Research
https://www.readbyqxmd.com/read/29581864/galectin-3-sensitized-melanoma-cell-lines-to-vemurafenib-plx4032-induced-cell-death-through-prevention-of-autophagy
#7
Silvina Odete Bustos, Gustavo José da Silva Pereira, Renata de Freitas Saito, Cristiane Damas Gil, Daniela Bertolli Zanatta, Soraya Soubhi Smaili, Roger Chammas
Melanoma is a current worldwide problem, as its incidence is increasing. In the last years, several studies have shown that melanoma cells display high levels of autophagy, a self-degradative process that can promote survival leading to drug resistance. Consequently, autophagy regulation represents a challenge for cancer therapy. Herein, we showed that galectin-3 (Gal-3), a β-galactoside binding lectin which is often lost along melanoma progression, is a negative regulator of autophagy in melanoma cells. Our data demonstrated that Gal-3low/negative cells were more resistant to the inhibition of the activity of the cancer driver gene BRAF V600E by vemurafenib (PLX4032)...
March 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29570393/a-new-role-for-herpud1-and-erad-activation-in-osteoblast-differentiation-and-mineralization
#8
Luan Américo-Da-Silva, Jheimmy Diaz, Mario Bustamante, Georthan Mancilla, Ingrid Oyarzún, Hugo E Verdejo, Clara Quiroga
Bone integrity depends on a finely tuned balance between bone synthesis by osteoblasts and resorption by osteoclasts. The secretion capacity of mature osteoblasts requires strict control of proteostasis. Endoplasmic reticulum-associated degradation (ERAD) prevents the accumulation of unfolded ER proteins via dislocation to the cytosol and degradation by the proteasome. The ER membrane protein, homocysteine-inducible endoplasmic reticulum protein with ubiquitin-like domain 1 (HERPUD1), is a key component of the ERAD multiprotein complex which helps to stabilize the complex and facilitate the efficient degradation of unfolded proteins...
March 23, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29570364/protein-quality-control-in-the-endoplasmic-reticulum-of-plants
#9
Richard Strasser
The endoplasmic reticulum (ER) is the site of maturation for roughly onethird of all cellular proteins. ER-resident molecular chaperones and folding catalysts promote folding and assembly in a diverse set of newly synthesized proteins. Because these processes are error-prone, all eukaryotic cells have a quality control system in place that constantly monitors the proteins and decides their fate. Proteins with potentially harmful nonnative conformations are subjected to assisted folding or degraded. Persistent folding-defective proteins are distinguished from folding intermediates and targeted for degradation by a specific process involving clearance from the ER...
March 23, 2018: Annual Review of Plant Biology
https://www.readbyqxmd.com/read/29563563/the-transcriptional-profiles-and-functional-implications-of-long-non-coding-rnas-in-the-unfolded-protein-response
#10
Hongyang Quan, Qianqian Fan, Chuang Li, Yan-Ying Wang, Lin Wang
The unfolded protein response (UPR) is activated, when the folding capacity is compromised in the endoplasmic reticulum (ER). To date, most studies focused on the coding genes and microRNAs in UPR. Other non-coding RNAs affected by UPR and their roles in UPR have not been systematically studied. Long noncoding RNAs (lncRNAs) are increasingly recognized as powerful epigenetic regulators. In this study, we transcriptomically profiled the lncRNAs and mRNAs from mouse embryonic fibroblasts under ER stress, and identified many differentially expressed lncRNAs and mRNAs...
March 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29562214/tissue-specific-molecular-and-cellular-toxicity-of-pb-in-the-oyster-crassostrea-gigas-mrna-expression-and-physiological-studies
#11
Jie Meng, Wen-Xiong Wang, Li Li, Guofan Zhang
Lead (Pb) is one of the ubiquitous and toxic elements in aquatic environment. In oysters, gills and digestive glands are the main target organs for Pb-induced toxicity, but there is limited information on the molecular mechanisms underlying its toxicity. The present study investigated the Pb-induced toxicity mechanisms in the Pacific oyster (Crassostrea gigas) based on transcriptome, phenotypic anchoring, and validation of targeted gene expression. Gene ontology and pathway enrichment analyses revealed the differential Pb toxicity mechanisms in the tissues...
March 13, 2018: Aquatic Toxicology
https://www.readbyqxmd.com/read/29555962/dissection-of-the-role-of-vimp-in-endoplasmic-reticulum-associated-degradation-of-cftr%C3%AE-f508
#12
Xia Hou, Hongguang Wei, Carthic Rajagopalan, Hong Jiang, Qingtian Wu, Khalequz Zaman, Youming Xie, Fei Sun
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functional activity of VIMP in ERAD remains to be understood. Here we investigate the role of VIMP in the degradation of CFTRΔF508, a cystic fibrosis transmembrane conductance regulator (CFTR) mutant known to be a substrate of ERAD...
March 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29544880/stress-associated-endoplasmic-reticulum-protein-1-serp1-and-atg8-synergistically-regulate-unfolded-protein-response-upr-that-is-independent-on-autophagy-in-candida-albicans
#13
Jianrong Li, Qilin Yu, Bing Zhang, Chenpeng Xiao, Tianyu Ma, Xiao Yi, Chao Liang, Mingchun Li
Cellular stresses could activate several response processes, such as the unfolded protein response (UPR), autophagy and oxidative stress response to restore cellular homeostasis or render cell death. Herein, we identified the Candida albicans stress-associated endoplasmic reticulum protein 1 (SERP1), also known as Ysy6, which was involved in endoplasmic reticulum (ER) stress response. We found that deletion of both SERP1/YSY6 and ATG8 led to hypersensitivity to tunicamycin (TN), and resulted in severe mitochondrial dysfunction under this stress...
March 6, 2018: International Journal of Medical Microbiology: IJMM
https://www.readbyqxmd.com/read/29534682/regulation-of-cnksr2-protein-stability-by-the-hect-e3-ubiquitin-ligase-smurf2-and-its-role-in-breast-cancer-progression
#14
Diana David, Arun Surendran, Jissa V Thulaseedharan, Asha S Nair
BACKGROUND: Smurf2 E3 ubiquitin ligase physically associates with and regulate the stability of distinct cellular protein substrates. The multi-functional scaffold protein Connector enhancer of kinase suppressor of ras 2 (CNKSR2) plays a key role in regulating cell proliferation, and differentiation through multiple receptor tyrosine kinase pathways. The aim of this study was to investigate whether the interaction between Smurf2 and CNKSR2 has any significant role in the post transcriptional regulation of CNKSR2 expression in breast cancer...
March 13, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29533745/the-impact-of-erad-on-recombinant-protein-secretion-in-pichia-pastoris-syn-komagataella-spp
#15
Richard J Zahrl, Diethard Mattanovich, Brigitte Gasser
The yeast Pichia pastoris (syn. Komagataella spp.) is a popular cell factory for recombinant protein production. Yeasts in general provide a good starting point for cell factory engineering. They are intrinsically robust and easy to manipulate and cultivate. However, their secretory pathway is not evolutionarily adapted to high loads of secretory protein. In particular, more complex proteins, like the antibody fragment (Fab) used in this study, overwhelm the folding and secretion capacity. This triggers cellular stress responses, which may cause excessive intracellular degradation...
March 13, 2018: Microbiology
https://www.readbyqxmd.com/read/29519897/march6-and-trc8-facilitate-the-quality-control-of-cytosolic-and-tail-anchored-proteins
#16
Sandra Stefanovic-Barrett, Anna S Dickson, Stephen P Burr, James C Williamson, Ian T Lobb, Dick Jh van den Boomen, Paul J Lehner, James A Nathan
Misfolded or damaged proteins are typically targeted for destruction by proteasome-mediated degradation, but the mammalian ubiquitin machinery involved is incompletely understood. Here, using forward genetic screens in human cells, we find that the proteasome-mediated degradation of the soluble misfolded reporter, mCherry-CL1, involves two ER-resident E3 ligases, MARCH6 and TRC8. mCherry-CL1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH6/TRC8 cells...
March 8, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29514927/a-vcp-inhibitor-substrate-trapping-approach-vista-enables-proteomic-profiling-of-endogenous-erad-substrates
#17
Edmond Y Huang, Milton To, Erica Tran, Lorraine T Ador Dionisio, Hyejin J Cho, Katherine L M Baney, Camille I Pataki, James A Olzmann
Endoplasmic reticulum (ER)-associated degradation (ERAD) mediates the proteasomal clearance of proteins from the early secretory pathway. In this process, ubiquitinated substrates are extracted from membrane-embedded dislocation complexes by the AAA ATPase VCP and targeted to the cytosolic 26S proteasome. In addition to its well-established role in the degradation of misfolded proteins, ERAD also regulates the abundance of key proteins such as enzymes involved in cholesterol synthesis. However, due to the lack of generalizable methods, our understanding of the scope of proteins targeted by ERAD remains limited...
March 7, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29504610/pi3k%C3%AE-contributes-to-er-stress-associated-asthma-through-er-redox-disturbances-the-involvement-of-the-ridd-rig-i-nf-%C3%AE%C2%BAb-axis
#18
Hyun-Kyoung Kim, Geum-Hwa Lee, Kashi Raj Bhattarai, Raghu Patil Junjappa, Hwa-Young Lee, Mallikarjun Handigund, Anu Marahatta, Bidur Bhandary, In-Hwan Baek, Jae Sung Pyo, Hye-Kyung Kim, Ok Hee Chai, Hyung-Ryong Kim, Yong-Chul Lee, Han-Jung Chae
Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3Kδ inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model...
February 16, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29496607/a-novel-modelling-mechanism-of-pael-receptor-and-gabarapl2-interaction-involved-in-parkinson-s-disease
#19
Priyanka Dutta, Leila Dargahi, Kara E O'Connell, Ashini Bolia, Banu Ozkan, Andreas W Sailer, Kumlesh K Dev
Parkin associated endothelin like receptor (PAELR) is G-protein coupled and ubiquitinated by parkin, promoting its degradation. In autosomal recessive Parkinson's disease, mutations in parkin lead to PAELR aggregation in the endoplasmic reticulum (ER), ER stress, neurotoxicity and cell death. We have identified previously that the protein kinase C interacting protein (PICK1) interacts with and regulates the expression and cell toxicity of PAELR. Here, we experimentally identify and provide in-silico modelling of a novel interaction between PAELR and GABARAPL2 (γ-aminobutyrate type A receptor associated protein like 2), which is an autophagosome-specific Ub-like protein implicated in vesicle trafficking and autophagy...
February 26, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29496332/abnormal-expression-of-er-quality-control-and-er-associated-degradation-proteins-in-the-dorsolateral-prefrontal-cortex-in-schizophrenia
#20
Pitna Kim, Madeline R Scott, James H Meador-Woodruff
Abnormalities in posttranslational protein modifications (PTMs) that regulate protein targeting, trafficking, synthesis, and function have been implicated in the pathophysiology of schizophrenia. The endoplasmic reticulum (ER) contains specialized machinery that facilitate protein synthesis, ER entry and exit, quality control, and post-translational processing, steps required for protein maturation. Dysregulation of these systems could represent potential mechanisms for abnormalities of neurotransmitter associated proteins in schizophrenia...
February 26, 2018: Schizophrenia Research
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