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ER-associated degradation

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https://www.readbyqxmd.com/read/28633019/edem-function-in-erad-protects-against-chronic-er-proteinopathy-and-age-related-physiological-decline-in-drosophila
#1
Michiko Sekiya, Akiko Maruko-Otake, Stephen Hearn, Yasufumi Sakakibara, Naoki Fujisaki, Emiko Suzuki, Kanae Ando, Koichi M Iijima
The unfolded protein response (UPR), which protects cells against accumulation of misfolded proteins in the ER, is induced in several age-associated degenerative diseases. However, sustained UPR activation has negative effects on cellular functions and may worsen disease symptoms. It remains unknown whether and how UPR components can be utilized to counteract chronic ER proteinopathies. We found that promotion of ER-associated degradation (ERAD) through upregulation of ERAD-enhancing α-mannosidase-like proteins (EDEMs) protected against chronic ER proteinopathy without inducing toxicity in a Drosophila model...
June 19, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28630040/endoplasmic-reticulum-associated-degradation-of-the-renal-potassium-channel-romk-leads-to-type-ii-bartter-syndrome
#2
Brighid M O'Donnell, Timothy D Mackie, Arohan R Subramanya, Jeffrey L Brodsky
Type II Bartter syndrome is caused by mutations in the Renal Outer Medullary Potassium (ROMK) channel but the molecular mechanisms underlying this disease are poorly defined. To rapidly screen for ROMK function, we developed a yeast expression system and discovered that yeast cells lacking endogenous potassium channels could be rescued by WT ROMK but not by ROMK proteins containing one of four Bartter mutations. We also found that the mutant proteins were significantly less stable than WT ROMK. However, their degradation was slowed in the presence of a proteasome inhibitor or when yeast cells contained mutations in the CDC48 or SSA1 gene, which is required for endoplasmic reticulum (ER)-associated degradation (ERAD)...
June 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28622300/the-als-linked-e102q-mutation-in-sigma-receptor-1-leads-to-er-stress-mediated-defects-in-protein-homeostasis-and-dysregulation-of-rna-binding-proteins
#3
Alice Dreser, Jan Tilmann Vollrath, Antonio Sechi, Sonja Johann, Andreas Roos, Alfred Yamoah, Istvan Katona, Saeed Bohlega, Dominik Wiemuth, Yuemin Tian, Axel Schmidt, Jörg Vervoorts, Marc Dohmen, Cordian Beyer, Jasper Anink, Eleonora Aronica, Dirk Troost, Joachim Weis, Anand Goswami
Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons (MNs) and their target muscles. Misfolded proteins which often form intracellular aggregates are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (ubiquitin proteasome system and autophagy) and RNA-binding protein homeostasis has recently been suggested as an integrated model that merges several ALS-associated proteins into a common pathophysiological pathway...
June 16, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28611990/structure-and-function-of-p97-and-pex1-6-type-ii-aaa-complexes
#4
REVIEW
Paul Saffert, Cordula Enenkel, Petra Wendler
Protein complexes of the Type II AAA+ (ATPases associated with diverse cellular activities) family are typically hexamers of 80-150 kDa protomers that harbor two AAA+ ATPase domains. They form double ring assemblies flanked by associated domains, which can be N-terminal, intercalated or C-terminal to the ATPase domains. Most prominent members of this family include NSF (N-ethyl-maleimide sensitive factor), p97/VCP (valosin-containing protein), the Pex1/Pex6 complex and Hsp104 in eukaryotes and ClpB in bacteria...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28586431/proteomic-analysis-of-calcium-effects-on-soybean-root-tip-under-flooding-and-drought-stresses
#5
Xin Wang, Setsuko Komatsu
Flooding and drought are disadvantageous environmental conditions that induce cytosolic calcium in soybean. To explore the effects of flooding- and drought-induced increase in calcium, a gel-free/label-free proteomic analysis was performed. Cytosolic calcium was decreased by blocking calcium channels in the endoplasmic reticulum (ER) and plasma membrane under both stresses. Calnexin, protein disulfide isomerase, heat shock proteins, and thioredoxin were predominately affected as the ER proteins in response to calcium, and ER-associated degradation-related proteins of HCP-like superfamily protein was upregulated under stress exposure and then downregulated...
June 6, 2017: Plant & Cell Physiology
https://www.readbyqxmd.com/read/28580641/melatonin-reduces-endoplasmic-reticulum-stress-and-corneal-dystrophy-associated-tgfbip-through-activation-of-endoplasmic-reticulum-associated-protein-degradation
#6
Seung-Il Choi, Eunhee Lee, Begum Akuzum, Jang Bin Jeong, Yong-Sun Maeng, Tae-Im Kim, Eung Kweon Kim
Endoplasmic reticulum (ER) stress is emerging as a factor for the pathogenesis of granular corneal dystrophy type 2 (GCD2). This study was designed to investigate the molecular mechanisms underlying the protective effects of melatonin on ER stress in GCD2. Our results showed that GCD2 corneal fibroblasts were more susceptible to ER stress-induced death than were wild-type cells. Melatonin significantly inhibited GCD2 corneal cell death, caspase-3 activation, and poly (ADP-ribose) polymerase 1 cleavage caused by the ER stress inducer, tunicamycin...
June 5, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28578400/lipid-droplet-associated-hydrolase-promotes-lipid-droplet-fusion-and-enhances-atgl-degradation-and-triglyceride-accumulation
#7
Young-Hwa Goo, Se-Hee Son, Antoni Paul
Lipid droplet (LD)-associated hydrolase (LDAH) is a newly identified LD protein abundantly expressed in tissues that predominantly store triacylglycerol (TAG). However, how LDAH regulates TAG metabolism remains unknown. We found that upon oleic acid loading LDAH translocalizes from the ER to newly formed LDs, and induces LD coalescence in a tubulin-dependent manner. LDAH overexpression and downregulation in HEK293 cells increase and decrease, respectively, TAG levels. Pulse and chase experiments show that LDAH enhances TAG biogenesis, but also decreases TAG turnover and fatty acid release from cells...
June 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28572047/er-stress-and-cancer-the-foxo-forkhead-transcription-factor-link
#8
REVIEW
Glowi Alasiri, Lavender Yuen-Nam Fan, Stefania Zona, Isabella Galeno Goldsbrough, Hui-Ling Ke, Holger Werner Auner, Eric Wing-Fai Lam
The endoplasmic reticulum (ER) is a cellular organelle with central roles in maintaining proteostasis due to its involvement in protein synthesis, folding, quality control, distribution and degradation. The accumulation of misfolded proteins in the ER lumen causes 'ER stress' and threatens overall cellular proteostasis. To restore ER homeostasis, cells evoke an evolutionarily conserved adaptive signalling and gene expression network collectively called the 'unfolded protein response (UPR)', a complex biological process which aims to restore proteostasis...
May 29, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28559891/systematic-optimization-of-protein-secretory-pathways-in-saccharomyces-cerevisiae-to-increase-expression-of-hepatitis-b-small-antigen
#9
Jiayuan Sheng, Hunter Flick, Xueyang Feng
Hepatitis B is a major disease that chronically infects millions of people in the world, especially in developing countries. Currently, one of the effective vaccines to prevent Hepatitis B is the Hepatitis B Small Antigen (HBsAg), which is mainly produced by the recombinant yeast Saccharomyces cerevisiae. In order to bring down the price, which is still too high for people in developing countries to afford, it is important to understand key cellular processes that limit protein expression. In this study, we took advantage of yeast knockout collection (YKO) and screened 194 S...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28552883/sel1l-dependent-substrates-require-derlin2-3-and-herp1-2-for-endoplasmic-reticulum-associated-degradation
#10
Takehiro Sugimoto, Satoshi Ninagawa, Shimpei Yamano, Tokiro Ishikawa, Tetsuya Okada, Shunichi Takeda, Kazutoshi Mori
Accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). The ATF6 pathway is one of the three major pathways in vertebrates. Although ATF6, a transmembrane-type glycoprotein in the ER, functions as a UPR sensor/transducer, it is an unstable protein with a half-life of approximately 2 h and is constitutively subjected to the ER-associated degradation system with the location of the misfolded part in the ER lumen (ERAD-L). ERAD-L substrates are delivered to the cytosol through the retrotranslocon, which likely contains HRD1 (E3), gp78 (E3), SEL1L (a partner of HRD1), Derlin1/2/3 and Herp1/2...
May 26, 2017: Cell Structure and Function
https://www.readbyqxmd.com/read/28539871/protein-quality-control-and-the-amyotrophic-lateral-sclerosis-frontotemporal-dementia-continuum
#11
Hamideh Shahheydari, Audrey Ragagnin, Adam K Walker, Reka P Toth, Marta Vidal, Cyril J Jagaraj, Emma R Perri, Anna Konopka, Jessica M Sultana, Julie D Atkin
Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28537876/activation-of-perk-branch-of-er-stress-mediates-homocysteine-induced-bkca%C3%A2-channel-dysfunction-in-coronary-artery-via-foxo3a-dependent-regulation-of-atrogin-1
#12
Wen-Tao Sun, Xiang-Chong Wang, Shiu-Kwong Mak, Guo-Wei He, Xiao-Cheng Liu, Malcolm John Underwood, Qin Yang
The molecular mechanism of endoplasmic reticulum (ER) stress in vascular pathophysiology remains inadequately understood. We studied the role of ER stress in homocysteine-induced impairment of coronary dilator function, with uncovering the molecular basis of the effect of ER stress on smooth muscle large-conductance Ca2+-activated K+ (BKCa) channels. The vasodilatory function of BKCa channels was studied in a myograph using endothelium-denuded porcine small coronary arteries. Primary cultured porcine coronary artery smooth muscle cells were used for mRNA and protein measurements and current recording of BKCa channels...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28536268/endoplasmic-reticulum-stress-induced-degradation-of-dnajb12-stimulates-bok-accumulation-and-primes-cancer-cells-for-apoptosis
#13
Pattarawut Sopha, Hong Yu Ren, Diane E Grove, Douglas M Cyr
DNAJB12 (JB12) is an endoplasmic reticulum (ER)-associated Hsp40 family protein that recruits Hsp70 to the ER surface to coordinate the function of ER-associated and cytosolic chaperone systems in protein quality control. Hsp70 is stress inducible, but paradoxically, we report here that JB12 was degraded by the proteasome during severe ER stress. Destabilized JB12 was degraded by ER-associated degradation (ERAD) complexes that contained HERP, Sel1L, and gp78. JB12 was the only ER-associated chaperone that was destabilized by reductive stress...
May 23, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28535794/mutation-site-and-context-dependent-effects-of-esr1-mutation-in-genome-edited-breast-cancer-cell-models
#14
Amir Bahreini, Zheqi Li, Peilu Wang, Kevin M Levine, Nilgun Tasdemir, Lan Cao, Hazel M Weir, Shannon L Puhalla, Nancy E Davidson, Andrew M Stern, David Chu, Ben Ho Park, Adrian V Lee, Steffi Oesterreich
BACKGROUND: Mutations in the estrogen receptor alpha (ERα) 1 gene (ESR1) are frequently detected in ER+ metastatic breast cancer, and there is increasing evidence that these mutations confer endocrine resistance in breast cancer patients with advanced disease. However, their functional role is not well-understood, at least in part due to a lack of ESR1 mutant models. Here, we describe the generation and characterization of genome-edited T47D and MCF7 breast cancer cell lines with the two most common ESR1 mutations, Y537S and D538G...
May 23, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28524086/dietary-green-pea-protects-against-dss-induced-colitis-in-mice-challenged-with-high-fat-diet
#15
Shima Bibi, Luís Fernando de Sousa Moraes, Noelle Lebow, Mei-Jun Zhu
Obesity is a risk factor for developing inflammatory bowel disease. Pea is unique with its high content of dietary fiber, polyphenolics, and glycoproteins, all of which are known to be health beneficial. We aimed to investigate the impact of green pea (GP) supplementation on the susceptibility of high-fat diet (HFD)-fed mice to dextran sulfate sodium (DSS)-induced colitis. Six-week-old C57BL/6J female mice were fed a 45% HFD or HFD supplemented with 10% GP. After 7-week dietary supplementation, colitis was induced by adding 2...
May 18, 2017: Nutrients
https://www.readbyqxmd.com/read/28512218/ubiquitin-and-atp-dependent-unfoldase-activity-of-p97-vcp%C3%A2-nploc4%C3%A2-ufd1l-is-enhanced-by-a-mutation-that-causes-multisystem-proteinopathy
#16
Emily E Blythe, Kristine C Olson, Vincent Chau, Raymond J Deshaies
p97 is a "segregase" that plays a key role in numerous ubiquitin (Ub)-dependent pathways such as ER-associated degradation. It has been hypothesized that p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the fundamental basis for this activity. To address this issue, we developed a soluble p97 substrate-Ub-GFP modified with K48-linked ubiquitin chains-for in vitro p97 activity assays...
May 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28512024/repurposing-of-proton-pump-inhibitors-as-first-identified-small-molecule-inhibitors-of-endo-%C3%AE-n-acetylglucosaminidase-engase-for-the-treatment-of-ngly1-deficiency-a-rare-genetic-disease
#17
Yiling Bi, Matthew Might, Hariprasad Vankayalapati, Balagurunathan Kuberan
N-Glycanase deficiency, or NGLY1 deficiency, is an extremely rare human genetic disease. N-Glycanase, encoded by the gene NGLY1, is an important enzyme involved in protein deglycosylation of misfolded proteins. Deglycosylation of misfolded proteins precedes the endoplasmic reticulum (ER)-associated degradation (ERAD) process. NGLY1 patients produce little or no N-glycanase (Ngly1), and the symptoms include global developmental delay, frequent seizures, complex hyperkinetic movement disorder, difficulty in swallowing/aspiration, liver dysfunction, and a lack of tears...
July 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28495679/autophagosome-formation-is-initiated-at-phosphatidylinositol-synthase-enriched-er-subdomains
#18
Taki Nishimura, Norito Tamura, Nozomu Kono, Yuta Shimanaka, Hiroyuki Arai, Hayashi Yamamoto, Noboru Mizushima
The autophagosome, a double-membrane structure mediating degradation of cytoplasmic materials by macroautophagy, is formed in close proximity to the endoplasmic reticulum (ER). However, how the ER membrane is involved in autophagy initiation and to which membrane structures the autophagy-initiation complex is localized have not been fully characterized. Here, we were able to biochemically analyze autophagic intermediate membranes and show that the autophagy-initiation complex containing ULK and FIP200 first associates with the ER membrane...
June 14, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28479060/the-highly-dynamic-nature-of-erdj5-is-key-to-efficient-elimination-of-aberrant-protein-oligomers-through-er-associated-degradation
#19
Ken-Ichi Maegawa, Satoshi Watanabe, Kentaro Noi, Masaki Okumura, Yuta Amagai, Michio Inoue, Ryo Ushioda, Kazuhiro Nagata, Teru Ogura, Kenji Inaba
ERdj5, composed of an N-terminal J domain followed by six thioredoxin-like domains, is the largest protein disulfide isomerase family member and functions as an ER-localized disulfide reductase that enhances ER-associated degradation (ERAD). Our previous studies indicated that ERdj5 comprises two regions, the N- and C-terminal clusters, separated by a linker loop and with distinct functional roles in ERAD. We here present a new crystal structure of ERdj5 with a largely different cluster arrangement relative to that in the original crystal structure...
June 6, 2017: Structure
https://www.readbyqxmd.com/read/28448495/dysregulation-of-inf2-mediated-mitochondrial-fission-in-spop-mutated-prostate-cancer
#20
Xiaofeng Jin, Jie Wang, Kun Gao, Pingzhao Zhang, Longfang Yao, Yan Tang, Lisha Tang, Jian Ma, Jiantao Xiao, Enceng Zhang, Jie Zhu, Bin Zhang, Shi-Min Zhao, Yao Li, Shancheng Ren, Haojie Huang, Long Yu, Chenji Wang
Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation...
April 2017: PLoS Genetics
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