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Protein folding in the ER

Vahid Ajamein, Gilda Eslami, Salman Ahmadian, Ali Khamesipour, Mourad Elloumi
Cutaneous leishmaniosis (CL) is treated with pentavalent antimony (SbV) as a first-line drug, while amphotericin B and paromomycin are potential alternatives in antimonial- resistant isolates. However, the mechanisms of drug resistance remain unclear. The present study analyses the gene expression of RNA polymerase II (RNAP II) and J-binding protein 1 (JBP1), and J-binding protein 2 (JBP2) in Leishmania major after exposure to drugs in vitro. L. major (MRHO/IR/75/ER) promastigotes were exposed to various concentrations of glucantime, paromomycin and amphotericin B for 72 hours...
2018: Annals of Parasitology
Reeder M Robinson, Leticia Reyes, Ravyn M Duncan, Haiyan Bian, Allen B Reitz, Yefim Manevich, Jesse J McClure, Matthew M Champion, C James Chou, Meahgen E Sharik, Marta Chesi, P Leif Bergsagel, Nathan G Dolloff
Multiple Myeloma (MM) is highly sensitive to disruptions in cellular protein homeostasis. Proteasome inhibitors (PIs) are initially effective in the treatment of MM, although cures are not achievable and the emergence of resistance limits the durability of responses. New therapies are needed for refractory patients, and those that combat resistance to standard of care agents would be particularly valuable. Screening of multiple chemical libraries for PI re-sensitizing compounds identified E61 as a potent enhancer of multiple PIs and MM specific activity...
October 12, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Katherine R Sadleir, Jelena Popovic, Robert Vassar
Alzheimer's disease (AD) mouse models that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1) form β-amyloid (Aβ) plaques, a hallmark AD lesion. It has been assumed that the neuroinflammation, synaptic dysfunction, neurodegeneration, and cognitive impairment observed in these mice are caused by cerebral Aβ accumulation. However, it is also possible that accumulation of overexpressed transmembrane proteins APP and PS1 in the endoplasmic reticulum (ER) triggers chronic ER stress and activation of the unfolded protein response (UPR)...
October 12, 2018: Journal of Biological Chemistry
Juan J Barrero, Jason C Casler, Francisco Valero, Pau Ferrer, Benjamin S Glick
BACKGROUND: Proteins can be secreted from a host organism with the aid of N-terminal secretion signals. The budding yeast Pichia pastoris (Komagataella sp.) is widely employed to secrete proteins of academic and industrial interest. For this yeast, the most commonly used secretion signal is the N-terminal portion of pre-pro-α-factor from Saccharomyces cerevisiae. However, this secretion signal promotes posttranslational translocation into the endoplasmic reticulum (ER), so proteins that can fold in the cytosol may be inefficiently translocated and thus poorly secreted...
October 12, 2018: Microbial Cell Factories
Hamid Mollazadeh, Stephen L Atkin, Alexandra E Butler, Massimiliao Ruscica, Cesare R Sirtori, Amirhossein Sahebkar
The endoplasmic reticulum (ER) is critical in protein processing and particularly in ensuring that proteins undergo their correct folding to exert their functionality. What is becoming increasingly clear is that the ER may undergo increasing stress brought about by nutrient deprivation, hypoxia, oxidized lipids, point mutations in secreted proteins, cellular differentiation or significant deviation from metabolic set points, and loss of Ca2+ homeostasis, with detrimental effects on ER-resident calcium-dependent chaperones, alone or in combination...
October 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Grace R Jeschke, Hua Jane Lou, Keith Weise, Charlotte I Hammond, Mallory Demonch, Patrick Brennwald, Benjamin E Turk
Multisite phosphorylation of proteins is a common mechanism for signal integration and amplification in eukaryotic signaling networks. Proteins are commonly phosphorylated at multiple sites in an ordered manner, whereby phosphorylation by one kinase primes the substrate by generating a recognition motif for a second kinase. Here we show that substrate priming promotes phosphorylation by Saccharomyces cerevisiae Kin1 and Kin2, kinases that regulate cell polarity, exocytosis, and the endoplasmic reticulum (ER) stress response...
October 10, 2018: Journal of Biological Chemistry
Daniela Sarnataro
The misfolding and aggregation of proteins is the neuropathological hallmark for numerous diseases including Alzheimer's disease, Parkinson's disease, and prion diseases. It is believed that misfolded and abnormal β-sheets forms of wild-type proteins are the vectors of these diseases by acting as seeds for the aggregation of endogenous proteins. Cellular prion protein (PrPC ) is a glycosyl-phosphatidyl-inositol (GPI) anchored glycoprotein that is able to misfold to a pathogenic isoform PrPSc , the causative agent of prion diseases which present as sporadic, dominantly inherited and transmissible infectious disorders...
October 9, 2018: International Journal of Molecular Sciences
Murali K Yanda, Qiangni Liu, Valeriu Cebotaru, William B Guggino, Liudmila Cebotaru
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in genes encoding the polycystin (PC) 1 and 2 proteins. The goal of this study was to determine the role of calcium in regulating cyst growth. Stromal interaction molecule 1 (STIM1) protein expression was 15-fold higher in PC1-null proximal tubule cells (PN) than in heterozygote (PH) controls and 2-fold higher in an inducible, PC1 knockout, mouse model of ADPKD compared to a non-cystic match control. IP3 receptor protein expression was also higher in the cystic mice...
October 5, 2018: Cellular Signalling
Renhong Yan, Hongwu Qian, Ivan Lukmantara, Mingming Gao, Ximing Du, Nieng Yan, Hongyuan Yang
The biogenesis of lipid droplets (LDs) and the development of adipocytes are two key aspects of mammalian fat storage. SEIPIN, an integral membrane protein of the endoplasmic reticulum (ER), plays a critical role in both LD formation and adipogenesis. The molecular function of SEIPIN, however, has yet to be elucidated. Here, we report the cryogenic electron microscopy structure of human SEIPIN at 3.8 Å resolution. SEIPIN exists as an undecamer, and this oligomerization state is critical for its physiological function...
September 28, 2018: Developmental Cell
Vanessa Capone, Emanuela Clemente, Elena Restelli, Antonella Di Campli, Samantha Sperduti, Francesca Ornaghi, Laura Pietrangelo, Feliciano Protasi, Roberto Chiesa, Michele Sallese
Loss-of-function mutations in the SIL1 gene are linked to Marinesco-Sjögren syndrome (MSS), a rare multisystem disease of infancy characterized by cerebellar and skeletal muscle degeneration. SIL1 is a ubiquitous adenine nucleotide exchange factor for the endoplasmic reticulum (ER) chaperone BiP. The complexity of mechanisms by which loss of SIL1 causes MSS is not yet fully understood. We used HeLa cells to test the hypothesis that impaired protein folding in the ER due to loss of SIL1 could affect secretory trafficking, impairing the transport of cargoes essential for the function of MSS vulnerable cells...
October 2018: Biochimica et biophysica acta. Molecular basis of disease
Stephanie van de Wall, Karl Ljungberg, Peng Peng Ip, Annemarie Boerma, Maria L Knudsen, Hans W Nijman, Peter Liljeström, Toos Daemen
Cervical cancer develops as a result of infection with high-risk human papillomavirus (HPV) through persistent expression of early proteins E6 and E7. Our group pioneered a recombinant viral vector system based on Semliki Forest virus (SFV) for vaccination against cervical cancer. The most striking benefit of this alphavirus vector-based vaccine platform is its high potency. DNA vaccines on the other hand, have a major advantage with respect to ease of production. In this study, the benefits associated with both SFV-based vaccines and DNA vaccines were combined with the development of a DNA-launched RNA replicon (DREP) vaccine targeting cervical cancer...
2018: Oncoimmunology
Yuancai Xiang, Meng Wang, Shaofan Hu, Lu Qiu, Fang Yang, Zhengwen Zhang, Siwang Yu, Jingbo Pi, Yiguo Zhang
To gain a better understanding of the multistep processing of Nrf1 to yield various isoforms with confused molecular masses, we herein establish a generally acceptable criterion required for identification of its endogenous full-length proteins and derivative isoforms expressed differentially in distinct experimental cell lines. Further work has been focused on the molecular mechanisms that dictate the successive post-translational modifications (i.e. glycosylation by OST, deglycosylation by NGLY, and ubiquitination by Hrd1) of this CNC-bZIP protein and its proteolytic processing to give rise to multiple proteoforms...
October 1, 2018: Toxicology and Applied Pharmacology
Hye Won Moon, Hye Gyeong Han, Young Joo Jeon
The endoplasmic reticulum (ER) is an essential compartment of the biosynthesis, folding, assembly, and trafficking of secretory and transmembrane proteins, and consequently, eukaryotic cells possess specialized machineries to ensure that the ER enables the proteins to acquire adequate folding and maturation for maintaining protein homeostasis, a process which is termed proteostasis. However, a large variety of physiological and pathological perturbations lead to the accumulation of misfolded proteins in the ER, which is referred to as ER stress...
October 3, 2018: International Journal of Molecular Sciences
Adrian B Mehrtash, Mark Hochstrasser
Numerous nascent proteins undergo folding and maturation within the luminal and membrane compartments of the endoplasmic reticulum (ER). Despite the presence of various factors in the ER that promote protein folding, many proteins fail to properly fold and assemble and are subsequently degraded. Regulatory proteins in the ER also undergo degradation in a way that is responsive to stimuli or the changing needs of the cell. As in most cellular compartments, the ubiquitin-proteasome system (UPS) is responsible for the majority of the degradation at the ER-in a process termed ER-associated degradation (ERAD)...
October 9, 2018: Seminars in Cell & Developmental Biology
Yonju Ha, Wei Liu, Hua Liu, Shuang Zhu, Fan Xia, Julia E Gerson, Nisha A Azhar, Ronald G Tilton, Massoud Motamedi, Rakez Kayed, Wenbo Zhang
Purpose: Retinal ganglion cell (RGC) death following axonal injury occurring in traumatic optic neuropathy (TON) causes irreversible vision loss. GRP78 is a molecular chaperone that enhances protein folding and controls activation of endoplasmic reticulum (ER) stress pathways. This study determined whether adeno-associated virus (AAV)-mediated gene transfer of GRP78 protected RGCs from death in a mouse model of TON induced by optic nerve crush (ONC). Methods: ONC was induced by a transient crush of optic nerve behind the eye globe...
September 4, 2018: Investigative Ophthalmology & Visual Science
Jianxin Yuan, Hongxia Wang, Yuancai Xiang, Shaofan Hu, Shaojun Li, Meng Wang, Lu Qiu, Yiguo Zhang
Among multiple distinct isoforms, Nrf1D is synthesized from a de novo translation of an alternatively-spliced transcript of Nrf1 mRNA, as accompanied by a naturally-occurring deletion of its stop codon-flanking 1466 nucleotides. This molecular event leads to the generation of a reading frameshift mutation, which results in a constitutive substitution of the intact Nrf1's C-terminal 72 amino acids (aa, covering the second half of the leucine zipper motif to C-terminal Neh3L domain) by an additional extended 80-aa stretch to generate a unique variant Nrf1D...
September 27, 2018: International Journal of Molecular Sciences
Evan A Bordt, Caroline J Smith, Tyler G Demarest, Staci D Bilbo, Marcy A Kingsbury
Neuroendocrine and immune signaling pathways are activated following insults such as stress, injury, and infection, in a systemic response aimed at restoring homeostasis. Mitochondrial metabolism and function have been implicated in the control of immune responses. Commonly studied along with mitochondrial function, reactive oxygen species (ROS) are closely linked to cellular inflammatory responses. It is also accepted that cells experiencing mitochondrial or endoplasmic reticulum (ER) stress induce response pathways in order to cope with protein-folding dysregulation, in homeostatic responses referred to as the unfolded protein responses (UPRs)...
September 27, 2018: Neurotoxicity Research
Giuliana Di Rocco, Silvia Baldari, Antonietta Gentile, Maurizio Capogrossi, Gabriele Toietta
BACKGROUND: Cell therapy for degenerative diseases aims at rescuing tissue damage by delivery of precursor cells. Thus far, this strategy has been mostly unsuccessful due to massive loss of donor cells shortly after transplantation. Several strategies have been applied to increase transplanted cell survival but only with limited success. The endoplasmic reticulum (ER) is an organelle involved in protein folding, calcium homeostasis, and lipid biosynthesis. Protein disulfide isomerase (PDI) is a molecular chaperone induced and activated by ER stress...
September 26, 2018: Stem Cell Research & Therapy
Ilchan Song, YangJoo Kang, Young Koung Lee, Soon-Chul Myung, Kisung Ko
The endoplasmic reticulum (ER) is the main site of protein synthesis, folding, and secretion to other organelles. The capacity of the ER to process proteins is limited, and excessive accumulation of unfolded and misfolded proteins can induce ER stress, which is associated with plant diseases. Here, a transgenic Arabidopsis system was established to express anti-cancer monoclonal antibodies (mAbs) that recognize the tumor-associated antigen GA733-2. Monoclonal antibody (mAb) CO17-1A recognize a tumor-associated epitope expressed on the colorectal cancer cell surface...
2018: PloS One
Joana B Serrano, Filipa Martins, Cátia D Pereira, Ans M M van Pelt, Odete A B da Cruz E Silva, Sandra Rebelo
TorsinA is a member of the AAA+ superfamily of adenosine triphosphatases. These AAA+ proteins have numerous biological functions, including vesicle fusion, cytoskeleton dynamics, intracellular trafficking, protein folding, and degradation as well as organelle biogenesis. Of particular interest is torsinA, which is mainly located in the endoplasmic reticulum (ER) and nuclear envelope (NE). Interestingly, mutations in the TOR1A gene (the gene encoding torsinA) are associated with DYT1 dystonia and with the preferential localization of mutated torsinA at the NE, where it is associated with lamina-associated polypeptide 1...
September 24, 2018: Microscopy and Microanalysis
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