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ER-associated degradation

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https://www.readbyqxmd.com/read/28933649/legionella-blocks-autophagy-by-cleaving-stx17-syntaxin-17
#1
Kohei Arasaki, Mitsuo Tagaya
Pathogens subvert host defense systems including autophagy and apoptosis for their survival and proliferation. Legionella pneumophila is a Gram-negative bacterium that grows in alveolar macrophages and causes severe pneumonia. Early during infection Legionella secretes effector proteins that convert the plasma membrane-derived vacuole containing Legionella into an endoplasmic reticulum (ER)-like replicative vacuole. These vacuoles ultimately fuse with the ER, where the pathogen replicates. Recently, we showed that one of the effectors, Lpg1137, is a serine protease that targets the mitochondria-associated ER membrane (MAM) and degrades STX17 (syntaxin 17), a SNARE implicated in macroautophagy/autophagy as well as mitochondria dynamics and membrane trafficking in fed cells...
September 21, 2017: Autophagy
https://www.readbyqxmd.com/read/28928140/selenoprotein-t-is-a-novel-ost-subunit-that-regulates-upr-signaling-and-hormone-secretion
#2
Abdallah Hamieh, Dorthe Cartier, Houssni Abid, André Calas, Carole Burel, Christine Bucharles, Cedric Jehan, Luca Grumolato, Marc Landry, Patrice Lerouge, Youssef Anouar, Isabelle Lihrmann
Selenoprotein T (SelT) is a recently characterized thioredoxin-like protein whose expression is very high during development, but is confined to endocrine tissues in adulthood where its function is unknown. We report here that SelT is required for adaptation to the stressful conditions of high hormone level production in endocrine cells. Using immunofluorescence and TEM immunogold approaches, we find that SelT is expressed at the endoplasmic reticulum membrane in all hormone-producing pituitary cell types. SelT knockdown in corticotrope cells promotes unfolded protein response (UPR) and ER stress and lowers endoplasmic reticulum-associated protein degradation (ERAD) and hormone production...
September 19, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28920921/increased-intracellular-proteolysis-reduces-disease-severity-in-an-er-stress-associated-dwarfism
#3
Lorna A Mullan, Ewa J Mularczyk, Louise H Kung, Mitra Forouhan, Jordan Ma Wragg, Royston Goodacre, John F Bateman, Eileithyia Swanton, Michael D Briggs, Raymond P Boot-Handford
The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28920920/er-associated-degradation-is-required-for-vasopressin-prohormone-processing-and-systemic-water-homeostasis
#4
Guojun Shi, Diane Somlo, Geun Hyang Kim, Cristina Prescianotto-Baschong, Shengyi Sun, Nicole Beuret, Qiaoming Long, Jonas Rutishauser, Peter Arvan, Martin Spiess, Ling Qi
Peptide hormones are crucial regulators of many aspects of human physiology. Mutations that alter these signaling peptides are associated with physiological imbalances that underlie diseases. However, the conformational maturation of peptide hormone precursors (prohormones) in the ER remains largely unexplored. Here, we report that conformational maturation of proAVP, the precursor for the antidiuretic hormone arginine-vasopressin, within the ER requires the ER-associated degradation (ERAD) activity of the Sel1L-Hrd1 protein complex...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28920918/mice-deficient-for-erad-machinery-component-sel1l-develop-central-diabetes-insipidus
#5
Daniel G Bichet, Yoann Lussier
Deficiency of the antidiuretic hormone arginine vasopressin (AVP) underlies diabetes insipidus, which is characterized by the excretion of abnormally large volumes of dilute urine and persistent thirst. In this issue of the JCI, Shi et al. report that Sel1L-Hrd1 ER-associated degradation (ERAD) is responsible for the clearance of misfolded pro-arginine vasopressin (proAVP) in the ER. Additionally, mice with Sel1L deficiency, either globally or specifically within AVP-expressing neurons, developed central diabetes insipidus...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28917050/preparation-of-selenocysteine-containing-forms-of-human-selenok-and-selenos
#6
Zhengqi Zhang, Jun Liu, Sharon Rozovsky
Selenoprotein K (SELENOK) and Selenoprotein S (SELENOS) are the members of the endoplasmic-reticulum-associated degradation (ERAD) complex, which is responsible for translocating misfolded proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Besides its involvement in the ERAD, SELENOK was shown to bind and stabilize the palmitoyl transferase DHHC6, and thus contributes to palmitoylation. SELENOK and SELENOS reside in the ER membrane by the way of a single transmembrane helix. Both contain an intrinsically disordered region with a selenocysteine (Sec) located one or two residues away from the C-terminus...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28906489/disrupting-cct-%C3%AE-%C3%A2-%C3%A2-%C3%AE-tubulin-selectively-kills-cct-%C3%AE-overexpressed-cancer-cells-through-mapks-activation
#7
Yan-Jin Liu, Vathan Kumar, Yuan-Feng Lin, Po-Huang Liang
We have previously demonstrated the ability of I-Trp to disrupt the protein-protein interaction of β-tubulin with chaperonin-containing TCP-1β (CCT-β). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT-β overexpression. In this study, we screened a panel of cancer cell lines, finding CCT-β overexpression in the triple-negative breast cancer cell line MDA-MB-231, colorectal cancer cell lines Colo205 and HCT116, and a gastric cancer cell line MKN-45...
September 14, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28881660/activation-of-perk-branch-of-er-stress-mediates-homocysteine-induced-bkca-channel-dysfunction-in-coronary-artery-via-foxo3a-dependent-regulation-of-atrogin-1
#8
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 Ca(2+)-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...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878084/human-herpesvirus-8-interleukin-6-interacts-with-calnexin-cycle-components-and-promotes-protein-folding
#9
Daming Chen, Qiwang Xiang, John Nicholas
Viral interleukin-6 (vIL-6) encoded by human herpesvirus 8 (HHV-8) is believed to contribute via mitogenic, survival, and angiogenic activities to HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease through autocrine or paracrine mechanisms during latency or productive replication. There is direct evidence that vIL-6 promotes latently infected PEL cell viability and proliferation and also viral productive replication in PEL and endothelial cells. These activities are mediated largely through endoplasmic reticulum (ER)-localized vIL-6, which can induce signal transduction via the gp130 signaling receptor, activating mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) signaling, and interactions of vIL-6 with the ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2)...
September 6, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28877262/the-er-retention-protein-rer1-promotes-alpha-synuclein-degradation-via-the-proteasome
#10
Hyo-Jin Park, Daniel Ryu, Mayur Parmar, Benoit I Giasson, Nikolaus R McFarland
Abnormal accumulation of α-synuclein (αSyn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating αSyn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer's disease proteins and negatively regulates amyloid-β peptide levels...
2017: PloS One
https://www.readbyqxmd.com/read/28869838/fgfr2-driven-signaling-counteracts-tamoxifen-effect-on-er%C3%AE-positive-breast-cancer-cells
#11
Lukasz Turczyk, Kamila Kitowska, Magdalena Mieszkowska, Kamil Mieczkowski, Dominika Czaplinska, Dominika Piasecka, Radzisław Kordek, Andrzej C Skladanowski, Piotr Potemski, Hanna M Romanska, Rafal Sadej
Signaling mediated by growth factors receptors has long been suggested as one of the key factors responsible for failure of endocrine treatment in breast cancer (BCa). Herein we present that in the presence of tamoxifen, FGFs (Fibroblast Growth Factors) promote BCa cell growth with the strongest effect being produced by FGF7. FGFR2 was identified as a mediator of FGF7 action and the FGFR2-induced signaling was found to underlie cancer-associated fibroblasts-dependent resistance to tamoxifen. FGF7/FGFR2-triggered pathway was shown to induce ER phosphorylation, ubiquitination and subsequent ER proteasomal degradation which counteracted tamoxifen-promoted ER stabilization...
August 31, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28867719/er-stress-and-disease-toward-prevention-and-treatment
#12
Masayuki Kaneko, Kazunori Imaizumi, Atsushi Saito, Soshi Kanemoto, Rie Asada, Koji Matsuhisa, Yosuke Ohtake
Secretory and membrane proteins are synthesized in ribosomes, then mature in the endoplasmic reticulum (ER), but if ER function is impaired, immature defective proteins accumulate in the ER. This situation is called ER stress: in response, a defensive mechanism called the unfolded protein response (UPR) is activated in cells to reduce the defective proteins. During the UPR, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and RNA-dependent protein kinase (PKR)-like ER kinase (PERK) are activated, stress signals are transduced to the outside of the ER, and various cell responses, including gene induction, occur...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28864287/age-related-cataracts-role-of-unfolded-protein-response-ca-2-mobilization-epigenetic-dna-modifications-and-loss-of-nrf2-keap1-dependent-cytoprotection
#13
REVIEW
Palsamy Periyasamy, Toshimichi Shinohara
Age-related cataracts are closely associated with lens chronological aging, oxidation, calcium imbalance, hydration and crystallin modifications. Accumulating evidence indicates that misfolded proteins are generated in the endoplasmic reticulum (ER) by most cataractogenic stresses. To eliminate misfolded proteins from cells before they can induce senescence, the cells activate a clean-up machinery called the ER stress/unfolded protein response (UPR). The UPR also activates the nuclear factor-erythroid-2-related factor 2 (Nrf2), a central transcriptional factor for cytoprotection against stress...
September 2017: Progress in Retinal and Eye Research
https://www.readbyqxmd.com/read/28827405/conserved-cytoplasmic-domains-promote-hrd1-ubiquitin-ligase-complex-formation-for-er-associated-degradation-erad
#14
Jasmin Schulz, Dönem Avci, Markus A Queisser, Aljona Gutschmidt, Lena-Sophie Dreher, Emma J Fenech, Norbert Volkmar, Yuki Hayashi, Thorsten Hoppe, John C Christianson
The mammalian ubiquitin ligase Hrd1 is the central component of a complex facilitating degradation of misfolded proteins during the ubiquitin-proteasome dependent process of ER-associated degradation (ERAD). Hrd1 associates with cofactors to execute ERAD, but their roles and how they assemble with Hrd1 are not well understood. Here we identify crucial cofactor interaction domains within Hrd1 and report a previously unrecognised evolutionarily conserved segment within the intrinsically disordered cytoplasmic domain of Hrd1 (termed the HAF-H domain), which engages complementary segments in the cofactors FAM8A1 and Herp...
August 21, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28815531/mitochondria-endoplasmic-reticulum-contact-sites-mediate-innate-immune-responses
#15
Takuma Misawa, Michihiro Takahama, Tatsuya Saitoh
Mitochondria and the endoplasmic reticulum (ER) are fundamental organelles that coordinate high-order cell functions. Mitochondria are centers of energy production, whereas the ER is responsible for folding, transport, and degradation of proteins. In addition to their specific functions, mitochondria and ER actively communicate with each other to promote a variety of cellular events, such as material transfer and signal transduction. Recent studies have shown the critical involvement of these organelles in regulation of the innate immune system, which functions in host defense...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28815021/toward-an-understanding-of-the-cdc48-p97-atpase
#16
REVIEW
Nicholas Bodnar, Tom Rapoport
A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. For example, in endoplasmic reticulum (ER)-associated protein degradation (ERAD), Cdc48/p97 pulls polyubiquitinated, misfolded proteins out of the ER and transfers them to the proteasome. Cdc48/p97 consists of an N-terminal domain and two ATPase domains (D1 and D2). Six Cdc48 monomers form a double-ring structure surrounding a central pore...
2017: F1000Research
https://www.readbyqxmd.com/read/28808322/neuroinflammation-alters-cellular-proteostasis-by-producing-endoplasmic-reticulum-stress-autophagy-activation-and-disrupting-erad-activation
#17
Cristina Pintado, Sandra Macías, Helena Domínguez-Martín, Angélica Castaño, Diego Ruano
Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role of acute lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular proteostasis. In particular, we focused on macroautophagy (hereinafter called autophagy) and endoplasmic reticulum-associated protein degradation (ERAD)...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28782635/withaferin-a-induced-impaired-autophagy-and-unfolded-protein-response-in-human-breast-cancer-cell-lines-mcf-7-and-mda-mb-231
#18
Kamalini Ghosh, Soumasree De, Srimoyee Mukherjee, Sayantani Das, Amar Nath Ghosh, Sumita Bandyopadhyay Sengupta
The autophagy-lysosome pathway and the ubiquitin-proteasome systems are the two major routes for eukaryotic intracellular protein clearance. Cancerous cells often display elevated protein synthesis and byproduct disposal, thus, inhibition of the protein degradation pathways became an emerging approach for cancer therapy. The present study revealed that withaferin-A (WA), the biologically active withanolide derived from Withania somnifera, initially induced formation of autophagosomes in human breast cancer cell-lines, MCF-7 and MDA-MB-231...
October 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28777470/crosstalk-of-er-stress-mediated-autophagy-and-er-phagy-involvement-of-upr-and-the-core-autophagy-machinery
#19
REVIEW
Shuling Song, Jin Tan, Yuyang Miao, Qiang Zhang
Endoplasmic reticulum (ER) stress, a common cellular stress response, is closely related to the activation of autophagy that is an important and evolutionarily conserved mechanism for maintaining cellular homeostasis. Autophagy induced by ER stress mainly includes the ER stress-mediated autophagy and ER-phagy. The ER stress-mediated autophagy is characterized by the generation of autophagosomes that include worn-out proteins, protein aggregates, and damaged organelles. While the autophagosomes of ER-phagy selectively include ER membranes, and the double membranes also derive, at least in part, from the ER...
August 4, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28770435/implication-of-endoplasmic-reticulum-stress-in-autism-spectrum-disorder
#20
Koichi Kawada, Seisuke Mimori
Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Disorders, Fifth Edition and is defined as a congenital impairment of the central nervous system. ASD may be caused by a chromosomal abnormality or gene mutation. However, these etiologies are insufficient to account for the pathogenesis of ASD. Therefore, we propose that the etiology and pathogenesis of ASD are related to the stress of the endoplasmic reticulum (ER). ER stress, induced by valproic acid, increased in ASD mouse model, characterized by an unfolded protein response that is activated by this stress...
August 2, 2017: Neurochemical Research
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