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ER associated degradation

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https://www.readbyqxmd.com/read/29241549/trafficking-mediated-sting-degradation-requires-sorting-to-acidified-endolysosomes-and-can-be-targeted-to-enhance-anti-tumor-response
#1
Vijay K Gonugunta, Tomomi Sakai, Vladislav Pokatayev, Kun Yang, Jianjun Wu, Nicole Dobbs, Nan Yan
STING is an endoplasmic reticulum (ER)-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING degradation requires ER exit and function of vacuolar ATPase complex. Late-stage STING vesicles are sorted to Rab7-positive endolysosomes for degradation. Based on analysis of existing structures, we also identified the helix amino acid 281 (aa281)-297 as a motif required for trafficking-mediated STING degradation...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/29238611/structural-basis-for-nucleotide-modulated-p97-association-with-the-er-membrane
#2
Wai Kwan Tang, Ting Zhang, Yihong Ye, Di Xia
Association of the cytosolic AAA (ATPases associated with various cellular activities) protein p97 to membranes is essential for various cellular processes including endoplasmic reticulum (ER)-associated degradation. The p97 consists of two ATPase domains and an N domain that interacts with numerous cofactors. The N domain of p97 is known to undergo a large nucleotide-dependent conformation switch, but its physiological relevance is unclear. Here we show p97 is recruited to canine ER membranes predominantly by interacting with VCP-interacting membrane protein (VIMP), an ER-resident protein...
2017: Cell Discovery
https://www.readbyqxmd.com/read/29236390/serum-glycomarkers-of-endoplasmic-reticulum-and-lysosomal-endosomal-system-stress-in-human-healthy-aging-and-diseases
#3
I U Pismenetskaya, T D Butters
To verify the idea that extracellular free oligosaccharides might be able to reflect the functional status of the endoplasmic reticulum (ER) and lysosomal-endosomal system, HPLC-profiles of serum-derived free oligosaccharides (FOS) in human healthy aging, acute myeloproliferative neoplasms, and cardiovascular pathologies were compared with intracellular glycans. After plasma deproteinization and FOS purification the oligosaccharides were labelled with anthranilic acid, separated into the neutral and charged with QAE Sephadex (Q25-120) chromatography and analysed using high-performance liquid chromatography (HPLC)...
January 2017: Ukrainian Biochemical Journal
https://www.readbyqxmd.com/read/29233968/hrd1-prevents-apoptosis-in-renal-tubular-epithelial-cells-by-mediating-eif2%C3%AE-ubiquitylation-and-degradation
#4
Yujie Huang, Yifei Sun, Yizhi Cao, Hui Sun, Min Li, Hui You, Dongming Su, Yanjiao Li, Xiubin Liang
Apoptosis of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. One factor that regulates important cellular processes like apoptosis and cell proliferation is HRD1, an E3 ubiquitin ligase that acts by promoting ubiquitylation and degradation of its target protein. However, the detailed mechanisms by which HRD1 acts as a regulator of apoptosis in renal tubular epithelial cells have not been established. In our previous liquid chromatography-tandem mass spectrometry (LC-MS/MS) study (Mol Endocrinol...
December 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29232193/testosterone-regulates-granzyme-k-expression-in-rat-testes
#5
Dibyendu Dutta, In Park, Hiwot Guililat, Samuel Sang, Arpita Talapatra, Barkha Singhal, Nathaniel C Mills
OBJECTIVE: Testosterone depletion induces increased germ cell apoptosis in testes. However, limited studies exist on genes that regulate the germ cell apoptosis. Granzymes (GZM) are serine proteases that induce apoptosis in various tissues. Multiple granzymes, including GZMA, GZMB and GZMN, are present in testes. Th us, we investigated which granzyme may be testosterone responsive and possibly may have a role in germ cell apoptosis aft er testosterone depletion. METHODS: Ethylene dimethane sulfonate (EDS), a toxicant that selectively ablates the Leydig cells, was injected into rats to withdraw the testosterone...
October 26, 2017: Endocrine Regulations
https://www.readbyqxmd.com/read/29230100/dl-3-n-butylphthalide-prevents-the-disruption-of-blood-spinal-cord-barrier-via-inhibiting-endoplasmic-reticulum-stress-following-spinal-cord-injury
#6
Binbin Zheng, Yulong Zhou, Hongyu Zhang, Guangyong Yang, Zhenghua Hong, Dandan Han, Qingqing Wang, Zili He, Yanlong Liu, Fenzan Wu, Xie Zhang, Songlin Tong, Huazi Xu, Jian Xiao
After spinal cord injury (SCI), the destruction of blood-spinal cord barrier (BSCB) is shown to accelerate gathering of noxious blood-derived components in the nervous system, leading to secondary neurodegenerative damages. SCI activates endoplasmic reticulum stress (ER stress), which is considered to evoke secondary damages of neurons and glia. Recent evidence indicates that Dl-3-n-butylphthalide (NBP) has the neuroprotective effect in ischaemic brain injury, but whether it has protective effects on SCI or not is largely unclear...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29213132/reducing-biomass-recalcitrance-by-heterologous-expression-of-a-bacterial-peroxidase-in-tobacco-nicotiana-benthamiana
#7
Ayalew Ligaba-Osena, Bertrand Hankoua, Kay DiMarco, Robert Pace, Mark Crocker, Jesse McAtee, Nivedita Nagachar, Ming Tien, Tom L Richard
Commercial scale production of biofuels from lignocellulosic feed stocks has been hampered by the resistance of plant cell walls to enzymatic conversion, primarily owing to lignin. This study investigated whether DypB, the lignin-degrading peroxidase from Rodococcus jostii, depolymerizes lignin and reduces recalcitrance in transgenic tobacco (Nicotiana benthamiana). The protein was targeted to the cytosol or the ER using ER-targeting and retention signal peptides. For each construct, five independent transgenic lines were characterized phenotypically and genotypically...
December 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29202016/inhibition-of-ngly1-inactivates-the-transcription-factor-nrf1-and-potentiates-proteasome-inhibitor-cytotoxicity
#8
Frederick M Tomlin, Ulla I M Gerling-Driessen, Yi-Chang Liu, Ryan A Flynn, Janakiram R Vangala, Christian S Lentz, Sandra Clauder-Muenster, Petra Jakob, William F Mueller, Diana Ordoñez-Rueda, Malte Paulsen, Naoko Matsui, Deirdre Foley, Agnes Rafalko, Tadashi Suzuki, Matthew Bogyo, Lars M Steinmetz, Senthil K Radhakrishnan, Carolyn R Bertozzi
Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. The efficacy of these drugs is frequently undermined by acquired resistance. One mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. This "bounce-back" response is achieved through a unique mechanism...
November 22, 2017: ACS Central Science
https://www.readbyqxmd.com/read/29167270/ubia-prenyltransferase-domain-containing-protein-1-modulates-hmg-coa-reductase-degradation-to-coordinate-synthesis-of-sterol-and-nonsterol-isoprenoids
#9
Marc M Schumacher, Dong-Jae Jun, Brittany M Johnson, Russell A DeBose-Boyd
UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. We previously reported that sterols stimulate binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG CoA reductase. UBIAD1 binding inhibits sterol-accelerated, ER-associated degradation (ERAD) of reductase, one of several mechanisms for feedback control of this rate-limiting enzyme in the branched pathway that produces cholesterol and nonsterol isoprenoids such as GGpp. Accumulation of GGpp in ER membranes triggers release of UBIAD1 from reductase, permitting its maximal ERAD and ER-to-Golgi transport of UBIAD1...
November 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29167172/podocytes-exhibit-a-specialized-protein-quality-control-employing-derlin-2-in-kidney-disease
#10
Guohui Ren, Nicholas J Tardi, Fumihiko Matsuda, Kwi Hye Koh, Phillip Ruiz, Changli Wei, Mehmet Mete Altintas, Hidde Ploegh, Jochen Reiser
Podocytes are terminally differentiated cells of the kidney filtration barrier with a limited proliferative capacity, and are the primary glomerular target for various sources of cellular stress. Accordingly, it is particularly important for podocytes to cope with stress efficiently to circumvent cell death and avoid compromising renal function. Improperly folded proteins within the endoplasmic reticulum (ER) are associated with increased cellular injury and cell death. To relieve ER stress, protein quality control mechanisms like ER-associated degradation (ERAD) are initiated...
November 22, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29155878/irhom2-is-essential-for-innate-immunity-to-rna-virus-by-antagonizing-er-and-mitochondria-associated-degradation-of-visa
#11
Wei-Wei Luo, Shu Li, Chen Li, Zhou-Qin Zheng, Pan Cao, Zhen Tong, Huan Lian, Su-Yun Wang, Hong-Bing Shu, Yan-Yi Wang
VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms...
November 20, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29152155/chibby-1-a-new-component-of-%C3%AE-catenin-signaling-in-chronic-myeloid-leukemia
#12
REVIEW
Manuela Mancini, Simona Soverini, Gabriele Gugliotta, Maria Alessandra Santucci, Gianantonio Rosti, Michele Cavo, Giovanni Martinelli, Fausto Castagnetti
Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as β-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on β-catenin involves the direct interaction with: The C-terminal activation domain of β-catenin, which hinders β-catenin binding with Tcf/Lef transcription factors hence repressing β-catenin transcriptional activation. 14-3-3 scaffolding proteins (σ or ξ), which drive CBY1 nuclear export into a stable tripartite complex with β-catenin. The relative proximity of C22orf2 gene encoding for CBY1 to the BCR breakpoint on chromosome 22q11, whose translocation and rearrangement with the c-ABL is the causative event of chronic myeloid leukemia (CML), suggested that gene haploinsufficiency may play a role in the disease pathogenesis and progression...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29144457/a-ubiquitin-dependent-signalling-axis-specific-for-alkbh-mediated-dna-dealkylation-repair
#13
Joshua R Brickner, Jennifer M Soll, Patrick M Lombardi, Cathrine B Vågbø, Miranda C Mudge, Clement Oyeniran, Renana Rabe, Jessica Jackson, Meagan E Sullender, Elyse Blazosky, Andrea K Byrum, Yu Zhao, Mark A Corbett, Jozef Gécz, Michael Field, Alessandro Vindigni, Geir Slupphaug, Cynthia Wolberger, Nima Mosammaparast
DNA repair is essential to prevent the cytotoxic or mutagenic effects of various types of DNA lesions, which are sensed by distinct pathways to recruit repair factors specific to the damage type. Although biochemical mechanisms for repairing several forms of genomic insults are well understood, the upstream signalling pathways that trigger repair are established for only certain types of damage, such as double-stranded breaks and interstrand crosslinks. Understanding the upstream signalling events that mediate recognition and repair of DNA alkylation damage is particularly important, since alkylation chemotherapy is one of the most widely used systemic modalities for cancer treatment and because environmental chemicals may trigger DNA alkylation...
November 16, 2017: Nature
https://www.readbyqxmd.com/read/29135079/cigarette-smoke-extract-and-isoprene-resulted-in-the-induction-of-apoptosis-and-autophagy-in-human-placenta-choriocarcinoma-jeg-3-cells
#14
Hae-Miru Lee, Kyung-Chul Choi
In this study, the effects of cigarette smoke (CS) on the induction of apoptosis via reactive oxygen species (ROS) production and endoplasmic reticulum stress (ER stress) of JEG-3 human choriocarcinoma cells were examined to confirm the relationship between CS and placenta development. Upon TUNEL assay, CS extract (3R4F; 0.3 and 2.1 μM) increased JEG-3 apoptosis. Western blot assay revealed that the protein expressions of p53, Bax, and CCAAT-enhancer-binding protein homologous protein (CHOP) increased, while the levels of Bcl-2 were reduced following CS extract treatment...
November 14, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/29133892/er-associated-degradation-regulates-alzheimer-s-amyloid-pathology-and-memory-function-by-modulating-%C3%AE-secretase-activity
#15
Bing Zhu, LuLin Jiang, Timothy Huang, Yingjun Zhao, Tongfei Liu, Yongwang Zhong, Xiaoguang Li, Alexandre Campos, Kenneth Pomeroy, Eliezer Masliah, Dongxian Zhang, Huaxi Xu
Endoplasmic-reticulum-associated degradation (ERAD) is an important protein quality control system which maintains protein homeostasis. Constituents of the ERAD complex and its role in neurodegeneration are not yet fully understood. Here, using proteomic and FRET analyses, we demonstrate that the ER protein membralin is an ERAD component, which mediates degradation of ER luminal and membrane substrates. Interestingly, we identify nicastrin, a key component of the γ-secretase complex, as a membralin binding protein and membralin-associated ERAD substrate...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29117944/small-molecule-sigma1-modulator-induces-autophagic-degradation-of-pd-l1
#16
Christina M Maher, Jeffrey D Thomas, Derick A Haas, Charles G Longen, Halley M Oyer, Jane Y Tong, Felix J Kim
Emerging evidence suggests that Sigma1 (SIGMAR1, also known as sigma-1 receptor) is a unique ligand-regulated integral membrane scaffolding protein that contributes to cellular protein and lipid homeostasis. Previously, we demonstrated that some small molecule modulators of Sigma1 alter endoplasmic reticulum (ER) associated protein homeostasis pathways in cancer cells, including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type 1 integral membrane glycoprotein that is co-translationally inserted into the ER and is processed and transported through the secretory pathway...
November 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29109534/natural-history-of-helicobacter-pylori-vaca-toxin-in-human-gastric-epithelium-in-vivo-vacuoles-and-beyond
#17
Vittorio Necchi, Patrizia Sommi, Alessandro Vanoli, Roberto Fiocca, Vittorio Ricci, Enrico Solcia
Uptake, intracellular trafficking and pathologic effects of VacA toxin from Helicobacter pylori have been widely investigated in vitro. However, no systematic analysis investigated VacA intracellular distribution and fate in H. pylori-infected human gastric epithelium in vivo, using ultrastructural immunocytochemistry that combines precise toxin localization with analysis of the overall cell ultrastructure and intercompartimental/interorganellar relationships. By immunogold procedure, in this study we investigated gastric biopsies taken from dyspeptic patients to characterize the overall toxin's journey inside human gastric epithelial cells in vivo...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29109174/orientia-tsutsugamushi-modulates-endoplasmic-reticulum-associated-degradation-to-benefit-its-growth
#18
Kyle G Rodino, Lauren VieBrock, Sean M Evans, Hong Ge, Allen L Richards, Jason A Carlyon
Orientia tsutsugamushi, an obligate intracellular bacterium that is auxotrophic for the aromatic amino acids and histidine, causes scrub typhus, a potentially deadly infection that threatens one billion people. O. tsutsugamushi growth is minimal during the first 24 to 48 h of infection, but becomes logarithmic thereafter. How the pathogen modulates cellular functions to support its growth is poorly understood. The unfolded protein response (UPR) is a cytoprotective pathway that relieves endoplasmic reticulum (ER) stress by promoting ER-associated degradation (ERAD) of misfolded proteins...
November 6, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/29107682/underlying-mechanisms-for-sterol-induced-ubiquitination-and-er-associated-degradation-of-hmg-coa-reductase
#19
REVIEW
Brittany M Johnson, Russell A DeBose-Boyd
Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids...
October 28, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29098149/regulation-of-ire1%C3%AE-by-the-small-molecule-inhibitor-4%C3%AE-8c-in-hepatoma-cells
#20
Claire Stewart, Andrea Estrada, Paul Kim, Dong Wang, Yuren Wei, Chris Gentile, Michael Pagliassotti
The unfolded protein response (UPR) is activated in response to impairments of the folding environment in the endoplasmic reticulum (ER). The most conserved arm of the UPR, inositol-requiring ER-to-nucleus signaling protein (IRE1α), has been linked to the regulation of a diverse array of cellular processes including ER-associated degradation, inflammatory signaling, cell proliferation and membrane biogenesis. Recent studies have utilized the selective, small molecule inhibitor, 4μ8c, to examine the role of IRE1α endoribonuclease (RNase) activity in various cell types including multiple myeloma, mouse embryonic fibroblasts and pancreatic beta cells [1-5]...
April 2017: Endoplasmic Reticulum Stress in Diseases
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