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ER associated degradation

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https://www.readbyqxmd.com/read/28322292/a-structure-and-chemical-genomics-based-approach-for-repositioning-of-drugs-against-vcp-p97-atpase
#1
Aldo Segura-Cabrera, Reshmi Tripathi, Xiaoyi Zhang, Lin Gui, Tsui-Fen Chou, Kakajan Komurov
Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28315680/selenoprotein-s-is-required-for-clearance-of-c99-through-endoplasmic-reticulum-associated-degradation
#2
Jun Ki Jang, Ki Jun Park, Jea Hwang Lee, Kwan Young Ko, Seongman Kang, Ick Young Kim
Amyloid beta precursor protein (APP) is normally cleaved by α-secretase, but can also be cleaved by β-secretase (BACE1) to produce C99 fragments in the endoplasmic reticulum (ER) membrane. C99 is subsequently cleaved to amyloid β (Aβ), the aggregation of which is known to cause Alzheimer's disease. Therefore, C99 removing is for preventing the disease. Selenoprotein S (SelS) is an ER membrane protein participating in endoplasmic reticulum-associated degradation (ERAD), one of the stages in resolving ER stress of misfolded proteins accumulated in the ER...
March 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28303141/the-function-of-fk506-binding-protein-13-in-protein-quality-control-protects-plasma-cells-from-endoplasmic-reticulum-stress-associated-apoptosis
#3
Mini Jeong, Eunkyeong Jang, Suk San Choi, Changhoon Ji, Kyungho Lee, Jeehee Youn
Plasma cells (PCs) are exposed to intense endoplasmic reticulum (ER) stress imposed by enormous rates of immunoglobulin (Ig) synthesis and secretion. Therefore, protein homeostasis is crucial for the survival of PCs, but its molecular mechanism remains largely unknown. Here, we found marked overexpression of FK506-binding protein 13 (FKBP13) in long-lived PCs from autoimmune mice and investigated its function using a plasmacytoma cell line secreting IgA. FKBP13 expression was induced largely in the lumen of ER in response to treatment with an ER stressor tunicamycin or overexpression of an adaptive unfolded protein response (UPR) protein X-box binding protein 1 (XBP1)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28291566/with-the-help-of-mom-mitochondrial-contributions-to-cellular-quality-control
#4
REVIEW
Ralf J Braun, Benedikt Westermann
Mitochondria are essential organelles because they have key roles in cellular energy metabolism and many other metabolic pathways. Several quality control systems have evolved to ensure that dysfunctional mitochondria are either repaired or eliminated. The activities of these pathways are crucial for cellular health because they maintain functional mitochondria. In addition, the cytosolic ubiquitin-proteasome system (UPS) and the mitochondria-associated degradation pathway (MAD) share some of their core components, are functionally tightly interconnected, and mutually modulate their activities...
March 10, 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/28286085/hspa5-gene-encoding-hsp70-chaperone-bip-in-the-endoplasmic-reticulum
#5
REVIEW
Jie Wang, Jessica Lee, David Liem, Peipei Ping
The HSPA5 gene (Ensembl ID: ENSG00000044574 (WTSI/EMBL-EBI, 2015)) encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen. As a highly conserved molecular chaperone, BiP assists in a wide range of folding processes via its two structural domains, a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). BiP is also an essential component of the translocation machinery for protein import into the ER, a regulator for Ca(2+) homeostasis in the ER, as well as a facilitator of ER-associated protein degradation (ERAD) via retrograde transportation of aberrant proteins across the ER membrane...
March 7, 2017: Gene
https://www.readbyqxmd.com/read/28279189/therapeutic-strategies-of-drug-repositioning-targeting-autophagy-to-induce-cancer-cell-death-from-pathophysiology-to-treatment
#6
REVIEW
Go J Yoshida
The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation...
March 9, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28278296/robust-growth-of-avirulent-phase-ii-coxiella-burnetii-in-bone-marrow-derived-murine-macrophages
#7
Diane C Cockrell, Carrie M Long, Shelly J Robertson, Jeffrey G Shannon, Heather E Miller, Lara Myers, Charles L Larson, Tregei Starr, Paul A Beare, Robert A Heinzen
Published data show that murine bone marrow-derived macrophages (BMDM) restrict growth of avirulent phase II, but not virulent phase I, Coxiella burnetii. Growth restriction of phase II bacteria is thought to result from potentiated recognition of pathogen-associated molecular patterns, which leads to production of inhibitory effector molecules. Past studies have used conditioned medium from L-929 murine fibroblasts as a source of macrophage-colony stimulating factor (M-CSF) to promote differentiation of bone marrow-derived myeloid precursors into macrophages...
2017: PloS One
https://www.readbyqxmd.com/read/28241148/cytosolic-proteostasis-through-importing-of-misfolded-proteins-into-mitochondria
#8
Linhao Ruan, Chuankai Zhou, Erli Jin, Andrei Kucharavy, Ying Zhang, Zhihui Wen, Laurence Florens, Rong Li
Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction. Although many neurodegenerative-disease-associated proteins can be found in mitochondria, it remains unclear how mitochondrial dysfunction and protein aggregation could be related. In dividing yeast cells, protein aggregates that form under stress or during ageing are preferentially retained by the mother cell, in part through tethering to mitochondria, while the disaggregase Hsp104 helps to dissociate aggregates and thereby enables refolding or degradation of misfolded proteins...
March 1, 2017: Nature
https://www.readbyqxmd.com/read/28228754/proofreading-of-peptide-mhc-complexes-through-dynamic-multivalent-interactions
#9
REVIEW
Christoph Thomas, Robert Tampé
The adaptive immune system is able to detect and destroy cells that are malignantly transformed or infected by intracellular pathogens. Specific immune responses against these cells are elicited by antigenic peptides that are presented on major histocompatibility complex class I (MHC I) molecules and recognized by cytotoxic T lymphocytes at the cell surface. Since these MHC I-presented peptides are generated in the cytosol by proteasomal protein degradation, they can be metaphorically described as a window providing immune cells with insights into the state of the cellular proteome...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28209512/n-glycan-dependent-cell-surface-expression-of-the-p2y2-receptor-and-n-glycan-independent-distribution-to-lipid-rafts
#10
Tetsuto Nakagawa, Chihiro Takahashi, Hitomi Matsuzaki, Shohei Takeyama, Shinpei Sato, Ayaka Sato, Yoshiyuki Kuroda, Hideyoshi Higashi
P2Y2 receptor (P2Y2R) is a G-protein-coupled receptor (GPCR) that couples with Gαq/11 and is stimulated by ATP and UTP. P2Y2R is involved in pain, proinflammatory changes, and blood pressure control. Some GPCRs are localized in lipid rafts for interaction with other signaling molecules. In this study, we prepared N-glycan-deficient mutants by mutating the two consensus Asn residues for N-glycosylation to Gln to examine intracellular localization and association with lipid rafts. Western blotting of the wild type (WT) protein and mutants (N9Q, N13Q, N9Q/N13Q) in COS-7 cells showed that both Asn residues were glycosylated in the WT...
April 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28208700/role-of-protein-quality-control-failure-in-alcoholic-hepatitis-pathogenesis
#11
REVIEW
Samuel W French, Maryam Masouminia, Sara Samadzadeh, Brittany C Tillman, Alejandro Mendoza, Barbara A French
The mechanisms of protein quality control in hepatocytes in cases of alcoholic hepatitis (AH) including ufmylation, FAT10ylation, metacaspase 1 (Mca1), ERAD (endoplasmic reticulum-associated degradation), JUNQ (juxta nuclear quality control), IPOD (insoluble protein deposit) autophagocytosis, and ER stress are reviewed. The Mallory-Denk body (MDB) formation develops in the hepatocytes in alcoholic hepatitis as a consequence of the failure of these protein quality control mechanisms to remove misfolded and damaged proteins and to prevent MDB aggresome formation within the cytoplasm of hepatocytes...
February 8, 2017: Biomolecules
https://www.readbyqxmd.com/read/28205568/luman-contributes-to-brefeldin-a-induced-prion-protein-gene-expression-by-interacting-with-the-erse26-element
#12
Marc-André Déry, Andréa C LeBlanc
The cellular prion protein (PrP) is essential for transmissible prion diseases, but its exact physiological function remains unclear. Better understanding the regulation of the human prion protein gene (PRNP) expression can provide insight into this elusive function. Spliced XBP1 (sXBP1) was recently shown to mediate endoplasmic reticulum (ER) stress-induced PRNP expression. In this manuscript, we identify Luman, a ubiquitous, non-canonical unfolded protein response (UPR), as a novel regulator of ER stress-induced PRNP expression...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28205175/membrane-extraction-of-hmg-coa-reductase-as-determined-by-susceptibility-of-lumenal-epitope-to-in-vitro-protease-digestion
#13
Lindsey L Morris, Russell A DeBose-Boyd
Although many aspects of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway have been elucidated, methods to detect and examine intermediate steps in the process are lacking. Here, we describe the use of a protease protection assay to study the metabolically regulated ERAD substrate HMG CoA reductase. Studies utilizing this assay reveal that ubiquitinated reductase becomes extracted across the ER membrane prior to its cytosolic release and proteasomal degradation through reactions mediated by distinct AAA-ATPases...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28197542/the-proline-arginine-dipeptide-from-hexanucleotide-repeat-expanded-c9orf72-inhibits-the-proteasome
#14
Rahul Gupta, Matthews Lan, Jelena Mojsilovic-Petrovic, Won Hoon Choi, Nathaniel Safren, Sami Barmada, Min Jae Lee, Robert Kalb
An intronic hexanucleotide repeat expansion (HRE) mutation in the C9ORF72 gene is the most common cause of familial ALS and frontotemporal dementia (FTD) and is found in ∼7% of individuals with apparently sporadic disease. Several different diamino acid peptides can be generated from the HRE by noncanonical translation (repeat-associated non-ATG translation, or RAN translation), and some of these peptides can be toxic. Here, we studied the effects of two arginine containing RAN translation products [proline/arginine repeated 20 times (PR20) and glycine/arginine repeated 20 times (GR20)] in primary rat spinal cord neuron cultures grown on an astrocyte feeder layer...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28159894/the-evolving-role-of-ubiquitin-modification-in-endoplasmic-reticulum-associated-degradation
#15
REVIEW
G Michael Preston, Jeffrey L Brodsky
The endoplasmic reticulum (ER) serves as a warehouse for factors that augment and control the biogenesis of nascent proteins entering the secretory pathway. In turn, this compartment also harbors the machinery that responds to the presence of misfolded proteins by targeting them for proteolysis via a process known as ER-associated degradation (ERAD). During ERAD, substrates are selected, modified with ubiquitin, removed from the ER, and then degraded by the cytoplasmic 26S proteasome. While integral membrane proteins can directly access the ubiquitination machinery that resides in the cytoplasm or on the cytoplasmic face of the ER membrane, soluble ERAD substrates within the lumen must be retrotranslocated from this compartment...
February 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28159754/reliance-of-wolbachia-on-high-rates-of-host-proteolysis-revealed-by-a-genome-wide-rnai-screen-of-drosophila-cells
#16
Pamela M White, Laura R Serbus, Alain Debec, Adan Codina, Walter Bray, Antoine Guichet, R Scott Lokey, William Sullivan
Wolbachia are gram-negative, obligate, intracellular bacteria carried by a majority of insect species worldwide. Here we use a Wolbachia-infected Drosophila cell line and genome-wide RNAi screening to identify host factors that influence Wolbachia titer. By screening an RNAi library targeting 15,699 transcribed host genes, we identified 36 candidate genes that dramatically reduced Wolbachia titer and 41 that increased Wolbachia titer. Host gene knockdowns that reduced Wolbachia titer spanned a broad array of biological pathways including genes that influenced mitochondrial function and lipid metabolism...
February 3, 2017: Genetics
https://www.readbyqxmd.com/read/28131906/a-novel-hdac6-inhibitor-tubastatin-a-controls-hdac6-p97-vcp-mediated-ubiquitination-autophagy-turnover-and-reverses-temozolomide-induced-er-stress-tolerance-in-gbm-cells
#17
Zong-Yang Li, Ce Zhang, Yuan Zhang, Lei Chen, Bao-Dong Chen, Qing-Zhong Li, Xie-Jun Zhang, Wei-Ping Li
Temozolomide (TMZ) is the cornerstone of therapy for glioblastoma multiforme (GBM). However, its efficacy is limited due to the development of multidrug resistance (MDR). In this study, we first identified the occurrence of ER stress-tolerance (ERST) in glioma cells and confirmed that ERST was positively correlated with TMZ resistance. We further showed that the seesaw-effect of HDAC6-p97/VCP (increased HDAC6 and decreased p97/VCP) in glioma cells was crucial to ERST-associated TMZ resistance. Moreover, the combination treatment of Tubastatin A (TUB, a selective inhibitor of HDAC6) and TMZ synergistically overcame ERST, reduced cell viability and induced apoptosis in TMZ-resistant glioma cells...
January 26, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28131647/new-insights-into-the-physiological-role-of-endoplasmic-reticulum-associated-degradation
#18
REVIEW
Ling Qi, Billy Tsai, Peter Arvan
Many human diseases are associated with mutations causing protein misfolding and aggregation in the endoplasmic reticulum (ER). ER-associated degradation (ERAD) is a principal quality-control mechanism responsible for targeting misfolded ER proteins for cytosolic degradation. However, despite years of effort, the physiological role of ERAD in vivo remains largely unknown. Several recent studies have reported intriguing phenotypes of mice deficient for ERAD function in specific cell types. These studies highlight that mammalian ERAD has been designed to perform a wide-range of cell-type-specific functions in vivo in a substrate-dependent manner...
February 8, 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/28125641/synergistic-action-of-genistein-and-calcitriol-in-immature-osteosarcoma-mg-63-cells-by-sgpl1-up-regulation
#19
Nadja Engel, Anna Adamus, Nicolas Schauer, Juliane Kühn, Barbara Nebe, Guido Seitz, Karin Kraft
BACKGROUND: Phytoestrogens such as genistein, the most prominent isoflavone from soy, show concentration-dependent anti-estrogenic or estrogenic effects. High genistein concentrations (>10 μM) also promote proliferation of bone cancer cells in vitro. On the other hand, the most active component of the vitamin D family, calcitriol, has been shown to be tumor protective in vitro and in vivo. The purpose of this study was to examine a putative synergism of genistein and calcitriol in two osteosarcoma cell lines MG-63 (early osteoblast), Saos-2 (mature osteoblast) and primary osteoblasts...
2017: PloS One
https://www.readbyqxmd.com/read/28121484/ubiquitin-ligase-syvn1-hrd1-facilitates-degradation-of-the-serpina1-z-variant-alpha-1-antitrypsin-z-variant-via-sqstm1-p62-dependent-selective-autophagy
#20
Lijie Feng, Jin Zhang, Na Zhu, Qian Ding, Xiaojie Zhang, Jishuang Yu, Weimin Qiang, Zhetao Zhang, Yuyang Ma, Dake Huang, Yujun Shen, Shengyun Fang, Yifan Yu, Haiping Wang, Yuxian Shen
SERPINA1/AAT/alpha-1-antitrypsin (serpin family A member 1) deficiency (SERPINA1/ AAT-D) is an autosomal recessive disorder characterized by the retention of misfolded SERPINA1/AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant reduction of serum SERPINA1/AAT level. The Z variant of SERPINA1/AAT, containing a Glu342Lys (E342K) mutation (SERPINA1(E342K)/ATZ), the most common form of SERPINA1/AAT-D, is prone to misfolding and polymerization, which retains it in the ER of hepatocytes and leads to liver injury...
January 25, 2017: Autophagy
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