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ER associated degradation

Douglas F Lake
The intracellular compartments for proteolytic antigen processing in tumor cells produce peptides that are presented by MHC molecules to T cells. But first, the ubiquitin ligase system tags defective, misfolded, aged, and unstable proteins for degradation through the proteasome. Ubiqitinated proteins are unfolded and fed into the barrel-shaped core of the proteasome where a collection of multiple different proteases cleave proteins into oligopeptides. After exiting the proteasome, these oligopeptides are either completely degraded into amino acids or trimmed at the N- and C-termini so that they bind to transporter associated with antigen processing (TAP)...
2017: Enzymes
Dong-Liang Jiao, Yan Chen, Yao Liu, Yun-Yue Ju, Jian-Dong Long, Jiang Du, Chang-Xi Yu, Yu-Jun Wang, Min Zhao, Jing-Gen Liu
Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABAAα1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was unclear. In the present study, we found that METH-induced CPP formation was accompanied by a significant increase in the expression of Synovial apoptosis inhibitor 1 (SYVN1), an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase, in the Dstr...
2017: Frontiers in Molecular Neuroscience
Donna Kennedy, Katarzyna Mnich, Deepu Oommen, Reka Chakravarthy, Leonardo Almeida-Souza, Michiel Krols, Svetlana Saveljeva, Karen Doyle, Sanjeev Gupta, Vincent Timmerman, Sophie Janssens, Adrienne M Gorman, Afshin Samali
BIM, a pro-apoptotic BH3-only protein, is a key regulator of the intrinsic (or mitochondrial) apoptosis pathway. Here, we show that BIM induction by endoplasmic reticulum (ER) stress is suppressed in rat PC12 cells overexpressing heat shock protein B1 (HSPB1 or HSP27) and that this is due to enhanced proteasomal degradation of BIM. HSPB1 and BIM form a complex that immunoprecipitates with p-ERK1/2. We found that HSPB1-mediated proteasomal degradation of BIM is dependent on MEK-ERK signaling. Other studies have shown that several missense mutations in HSPB1 cause the peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, which is associated with nerve degeneration...
August 31, 2017: Cell Death & Disease
Dylan A Frabutt, Bin Wang, Sana Riaz, Richard C Schwartz, Yong-Hui Zheng
Innate immunity provides an immediate defense against infection after host cells sense "danger" signals from microbes. Endoplasmic reticulum (ER) stress arises from accumulation of misfolded/unfolded proteins when protein load overwhelms the ER folding capacity, which activates the unfolded protein response (UPR) to restore the ER homeostasis. Here, we show that a mechanism for antiviral innate immunity is triggered after the ER stress pathway senses viral glycoproteins. When hemagglutinin (HA) glycoproteins from influenza A virus (IAV) are expressed in cells, ER stress is induced, resulting in rapid HA degradation via proteasomes...
October 18, 2017: Journal of Virology
Sophannary Kong, Akira Aoki, Kengo Iwasaki, Koji Mizutani, Sayaka Katagiri, Tomonari Suda, Shizuko Ichinose, Mayumi Ogita, Verica Pavlic, Yuichi Izumi
We investigated the biological effects of Er:YAG laser (2,940-nm; DELight(®) , HOYA ConBio, USA) irradiation at fluences of 3.6, 4.2, 4.9, 6.3, 8.1, or 9.7 J cm(-2) at 20 or 30 Hz for 20 or 30 s on primary human gingival fibroblasts (HGFs). Irradiation at 6.3 J cm(-2) promoted maximal cell proliferation, determined by WST-8 assay and crystal violet staining, but was accompanied by lactate dehydrogenase release, on day 3 post-irradiation. Elevation of ATP level, Ki67 staining, and cyclin-A2 mRNA expression confirmed that Er:YAG affected the cell cycle and increased the number of proliferating cells...
October 17, 2017: Journal of Biophotonics
Hadas Peled-Zehavi, Gad Galili
Macroautophagy (hereafter referred to as autophagy) is a conserved mechanism in eukaryotic cells that delivers unneeded cellular components for degradation in the lytic organelle. In plants, as in other eukaryotes, autophagy begins in the formation of cup-shaped double membranes that engulf cytosolic material. The double membrane closes to form autophagosomes that are then transported to the vacuole for degradation. Autophagy can function as a bulk nonselective process or as a selective process targeting specific proteins, protein aggregates, organelles, or other cellular components for degradation...
2018: Methods in Molecular Biology
Jennifer Schoberer, Yun-Ji Shin, Ulrike Vavra, Christiane Veit, Richard Strasser
Protein N-glycosylation is an essential posttranslational modification which is initiated in the endoplasmic reticulum. In plants, the N-glycans play a pivotal role for protein folding and quality control. Through the interaction of glycan processing and binding reactions mediated by ER-resident glycosidases and specific carbohydrate binding proteins, the N-glycans contribute to the adoption of a native protein conformation. Properly folded glycoproteins are released from these processes and allowed to continue their transit to the Golgi where further processing and maturation of N-glycans leads to the formation of more complex structures with different functions...
2018: Methods in Molecular Biology
Satoko Aratani, Hidetoshi Fujita, Naoko Yagishita, Yoshihisa Yamano, Yukari Okubo, Kusuki Nishioka, Toshihiro Nakajima
Rheumatoid arthritis (RA) is a chronic inflammatory articular disease that is characterized by synovial hyperplasia. A number of signaling pathways are associated with the development and induced symptoms of RA. Notably, patients with RA have increased protein citrullination and generation of auto‑antibodies against citrullinated proteins. Genome wide association studies have revealed that peptidyl‑arginine deiminase 4 (PADI4) is an enzyme implicated in citrullination in the RA synovium. Autoantibodies targeting citrullinated proteins are used as diagnostic markers in patients with RA...
October 11, 2017: Molecular Medicine Reports
Shuang-Xiang Tan, Di-Xuan Jiang, Rui-Cheng Hu, Ai-Guo Dai, Gui-Xiang Gan, Dai-Yan Fu, Chun-Chu Kong, Yun-Rong Chen, Li-Le Wang, Jie Li
BACKGROUND/AIMS: Cigarette smoking is a major risk factor of chronic obstructive pulmonary disease. This study aimed to examine the effects of cigarette smoke extract (CSE) on alveolar type II epithelial cells (AECII) and investigate the underlying mechanism. METHODS: Primary AECII were isolated from rat lung tissues and exposed to CSE. Apoptosis was detected by flow cytometry. Protein expression was detected by Western blot analysis. RESULTS: Primary rat AECII maintained morphological and physiological characteristic after 3 passages...
October 9, 2017: Cellular Physiology and Biochemistry
Susan J Allison
No abstract text is available yet for this article.
October 9, 2017: Nature Reviews. Nephrology
Tao Wang, Bei Wang, He Huang, Chongyang Zhang, Yuanmei Zhu, Bin Pei, Chaofei Cheng, Lei Sun, Jianwei Wang, Qi Jin, Zhendong Zhao
Endoplasmic reticulum-associated degradation (ERAD) is an important function for cellular homeostasis. The mechanism of how picornavirus infection interferes with ERAD remains unclear. In this study, we demonstrated that enterovirus 71 (EV71) infection significantly inhibits cellular ERAD by targeting multiple key ERAD molecules with its proteases 2Apro and 3Cpro using different mechanisms. Ubc6e was identified as the key E2 ubiquitin-conjugating enzyme in EV71 disturbed ERAD. EV71 3Cpro cleaves Ubc6e at Q219G, Q260S, and Q273G...
October 2017: PLoS Pathogens
Bianca Schaefer, Soenke Behrends
Heme oxygenase-1 (HO-1) degrades heme to bilirubin. In addition, it is upregulated in malignant disease and has been described as an important factor for cancer prognosis and therapy. Under physiological conditions HO-1 is anchored to the endoplasmic reticulum (ER). Under stress conditions HO-1 can be cleaved and subsequently translocates to the cytosol and nucleus. In this study we systematically investigated the influence of HO-1's catabolic activity and subcellular localization on resistance against the tyrosine kinase inhibitor imatinib in leukemia cells by confocal laser scanning microscopy, hemoglobin synthesis experiments and cell viability assays...
September 15, 2017: Oncotarget
Wenfang S Wu, Liang Zhu, Saurabh Patil, Karthiga Gokul, Sean O'Reilly, Joyce Chan, Poornima Tekumalla, Vivek Vishnudas, Michael A Kiebish, Rangaprasad Sarangarajan, Viatcheslav R Akmaev, Mark D Kellogg, Niven R Narain
Coiled-Coil Domain Containing 47 (CCDC47) is an endoplasmic reticulum (ER) transmembrane protein involved in calcium signaling through utilization of its calcium binding-acidic luminal domain. CCDC47 also interacts with ERAD (endoplasmic reticulum-associated degradation) complex and is involved in ER stress relief. In this report, we developed human CCDC47 monoclonal antibodies and a sandwich immunoassay for CCDC47 measurement in biological matrices. Specificity of developed antibodies were confirmed by immunoblot and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of immunoprecipitated cell lysates...
September 30, 2017: Journal of Immunological Methods
A M Masudul Azad Chowdhury, Hiroki Katoh, Atsushi Hatanaka, Hiroko Iwanari, Nanami Nakamura, Takao Hamakubo, Tohru Natsume, Tsuyoshi Waku, Akira Kobayashi
Accumulated evidence suggests a physiological relationship between the transcription factor NRF3 (NFE2L3) and cancers. Under physiological conditions, NRF3 is repressed by its endoplasmic reticulum (ER) sequestration. In response to unidentified signals, NRF3 enters the nucleus and modulates gene expression. However, molecular mechanisms underlying the nuclear translocation of NRF3 and its target gene in cancer cells remain poorly understood. We herein report that multiple regulation of NRF3 activities controls cell proliferation...
October 2, 2017: Scientific Reports
Hidetsugu Maekawa, Yoshiteru Tada, Kenji Yagi, Takeshi Miyamoto, Keiko T Kitazato, Masaaki Korai, Junichiro Satomi, Tomoki Hashimoto, Shinji Nagahiro
BACKGROUND: Estrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. Estrogen replacement therapy appears to reduce this risk but is associated with significant side effects. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats. METHODS: Ten-week-old female Sprague-Dawley rats were subjected to ovariectomy, hemodynamic changes, and hypertension to induce aneurysms (ovariectomized aneurysm rats) and treated with vehicle or with 0...
October 2, 2017: Journal of Neuroinflammation
Jianyu Cai, Xiaohong Xia, Yuning Liao, Ningning Liu, Zhiqiang Guo, Jinghong Chen, Li Yang, Huidan Long, Qianqian Yang, Xiaolan Zhang, Lu Xiao, Xuejun Wang, Hongbiao Huang, Jinbao Liu
Prostate cancer (PCa) remains a leading cause of cancer-related death in men. Especially, a subset of patients will eventually progress to the metastatic castrate-resistant prostate cancer (CRPC) which is currently incurable. Deubiquitinases (DUBs) associated with the 19S proteasome regulatory particle are increasingly emerging as significant therapeutic targets in numerous cancers. Recently, a novel small molecule b-AP15 is identified as an inhibitor of the USP14/UCHL5 (DUBs) of the 19S proteasome, resulting in cell growth inhibition and apoptosis in several human cancer cell lines...
September 8, 2017: Oncotarget
Khadija G Syeda, Anjan Kowluru
BACKGROUND/AIMS: Lamins are intermediate filament proteins that constitute the main components of the lamina underlying the inner-nuclear membrane and serve to organize chromatin. Lamins (e.g., lamin B) undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications are thought to render optimal association of lamins with the nuclear envelop. Using human islets, rodent islets, and INS-1 832/13 cells, we recently reported significant metabolic defects under glucotoxic and endoplasmic reticulum (ER) stress conditions, including caspase 3 activation and lamin B degradation...
October 2, 2017: Cellular Physiology and Biochemistry
Changhe Fu, Su Deng, Guangxu Jin, Xinxin Wang, Zu-Guo Yu
BACKGROUND: Molecular interaction data at proteomic and genetic levels provide physical and functional insights into a molecular biosystem and are helpful for the construction of pathway structures complementarily. Despite advances in inferring biological pathways using genetic interaction data, there still exists weakness in developed models, such as, activity pathway networks (APN), when integrating the data from proteomic and genetic levels. It is necessary to develop new methods to infer pathway structure by both of interaction data...
September 21, 2017: BMC Systems Biology
(no author information available yet)
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis...
December 2016: Molecular Oncology
Nicholas R Guydosh, Phillip Kimmig, Peter Walter, Rachel Green
The unfolded protein response (UPR) monitors and adjusts the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, the ER membrane-resident kinase/endoribonuclease Ire1 utilizes a mechanism of selective degradation of ER-bound mRNAs (RIDD) to maintain homeostasis. We used a genetic screen to identify factors critical to the Ire1-mediated UPR and found several proteins, Dom34, Hbs1 and Ski complex subunits, previously implicated in ribosome rescue and mRNA no-go-decay (NGD). Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage of ER-associated mRNAs results in ribosome stalling and mRNA degradation...
September 25, 2017: ELife
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