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ER-associated degradation

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
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
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
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
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
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
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
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
Ida Annunziata, Renata Sano, Alessandra d'Azzo
Lysosomal storage diseases (LSDs) comprise a large group of disorders of catabolism, mostly due to deficiency of a single glycan-cleaving hydrolase. The consequent endo-lysosomal accumulation of undigested or partially digested substrates in cells of virtually all organs, including the nervous system, is diagnostic of these diseases and underlies pathogenesis. A subgroup of LSDs, the glycosphingolipidoses, are caused by deficiency of glycosidases that process/degrade sphingolipids and glycosphingolipids (GSLs)...
February 28, 2018: Cell Death & Disease
Nicholas Nikesitch, James M Lee, Silvia Ling, Tara Laurine Roberts
Multiple myeloma (MM) is a haematological malignancy of mature antibody-secreting plasma cells. Currently, MM is incurable, but advances in drug treatments have increased patient lifespan. One of the characteristics of MM is the excessive production of monoclonal immunoglobulin (also referred to as paraprotein). This high level of protein production induces endoplasmic reticulum (ER) stress, and proteasomal degradation of the paraprotein is required to avoid ER stress-induced cell death. Consequently, proteasomal inhibitors such as bortezomib have been particularly effective therapies...
2018: Clinical & Translational Immunology
Nicholas Forsythe, Alaa Refaat, Arman Javadi, Hajrah Khawaja, Jessica-Anne Weir, Heba Emam, Wendy L Allen, Frank Burkamp, Vlad Popovici, Puthen V Jithesh, Claudio Isella, Melissa J LaBonte, Ian G Mills, Patrick G Johnston, Sandra Van Schaeybroeck
BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome...
February 26, 2018: Molecular Cancer Therapeutics
Fabienne Aregger, Dominik E Uehlinger, Gerhard Fusch, Aldin Bahonjic, Rene Pschowski, Michael Walter, Joerg C Schefold
BACKGROUND: Acute kidney injury (AKI) is often observed in critically ill patients and is associated with high morbidity and mortality. Non-recovery from AKI has a negative impact on the prognosis of affected patients and early risk stratification seems key to improve clinical outcomes. We analyzed metabolites of a conserved key inflammatory pathway (i.e. tryptophan degradation pathway) in serial urine samples of patients with AKI. METHODS: One hundred twelve ICU patients with AKI were included in a prospective observational analysis...
February 26, 2018: BMC Nephrology
Daniel Hughes, Giovanna R Mallucci
The unfolded protein response (UPR) is a highly conserved protein quality control mechanism, activated in response to Endoplasmic Reticulum (ER) stress. Signaling is mediated through three branches, PERK, IRE1 and ATF6, respectively, that together provide a coordinated response that contributes to overcoming disrupted proteostasis. PERK branch activation predominantly causes a rapid reduction in global rates of translation, whilst the IRE1 and ATF6 branch signaling induce a transcriptional response resulting in expression of chaperones and components of the protein degradation machinery...
February 24, 2018: FEBS Journal
Bowen Liu, Tianjiao Wang, Huawei Wang, Lu Zhang, Feifei Xu, Runping Fang, Leilei Li, Xiaoli Cai, Yue Wu, Weiying Zhang, Lihong Ye
BACKGROUND: Resistance to tamoxifen (TAM) frequently occurs in the treatment of estrogen receptor positive (ER+) breast cancer. Accumulating evidences indicate that transcription factor HOXB13 is of great significance in TAM resistance. However, the regulation of HOXB13 in TAM-resistant breast cancer remains largely unexplored. Here, we were interested in the potential effect of HBXIP, an oncoprotein involved in the acceleration of cancer progression, on the modulation of HOXB13 in TAM resistance of breast cancer...
February 23, 2018: Journal of Hematology & Oncology
Xiaoding Wang, Lin Xu, Thomas G Gillette, Xuejun Jiang, Zhao V Wang
Ischemic heart disease is a severe stress condition that causes extensive pathological alterations and triggers cardiac cell death. Accumulating evidence suggests that the unfolded protein response (UPR) is strongly induced by myocardial ischemia. The UPR is an evolutionarily conserved cellular response to cope with protein-folding stress, from yeast to mammals. Endoplasmic reticulum (ER) transmembrane sensors detect the accumulation of unfolded proteins and stimulate a signaling network to accommodate unfolded and misfolded proteins...
February 20, 2018: Journal of Molecular and Cellular Cardiology
Katalin Völgyi, Kata Badics, Fernando J Sialana, Péter Gulyássy, Edina Brigitta Udvari, Viktor Kis, László Drahos, Gert Lubec, Katalin Adrienna Kékesi, Gábor Juhász
Intracellular β-amyloid (Aβ) accumulation is an early event in Alzheimer's disease (AD) progression. Recently, it has been uncovered that presenilins (PSs), the key components of the amyloid precursor protein (APP) processing and the β-amyloid producing γ-secretase complex, are highly enriched in a special sub-compartment of the endoplasmic reticulum (ER) functionally connected to mitochondria, called mitochondria-associated ER membrane (MAM). A current hypothesis of pathogenesis of Alzheimer's diseases (AD) suggests that MAM is involved in the initial phase of AD...
February 22, 2018: Molecular Neurobiology
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
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
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
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
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