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Intracellular Degradation of Helicobacter pylori VacA Toxin as a Determinant of Gastric Epithelial Cell Viability.
Foegeding NJ, Raghunathan K, Campbell AM, Kim SW, Lau KS, Kenworthy AK, Cover TL, Ohi MD
(2019) Infect Immun 87:
MeSH Terms: Autophagy, Bacterial Proteins, Cell Line, Cell Survival, Epithelial Cells, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Hydrogen-Ion Concentration, Muramidase, Protein Stability, Protein Transport, Proteolysis
Show Abstract · Added February 7, 2019
VacA is a secreted pore-forming toxin that induces cell vacuolation and contributes to the pathogenesis of gastric cancer and peptic ulcer disease. We observed that purified VacA has relatively little effect on the viability of AGS gastric epithelial cells, but the presence of exogenous weak bases such as ammonium chloride (NHCl) enhances the susceptibility of these cells to VacA-induced vacuolation and cell death. Therefore, we tested the hypothesis that NHCl augments VacA toxicity by altering the intracellular trafficking of VacA or inhibiting intracellular VacA degradation. We observed VacA colocalization with LAMP1- and LC3-positive vesicles in both the presence and absence of NHCl, indicating that NHCl does not alter VacA trafficking to lysosomes or autophagosomes. Conversely, we found that supplemental NHCl significantly increases the intracellular stability of VacA. By conducting experiments using chemical inhibitors, stable ATG5 knockdown cell lines, and ATG16L1 knockout cells (generated using CRISPR/Cas9), we show that VacA degradation is independent of autophagy and proteasome activity but dependent on lysosomal acidification. We conclude that weak bases like ammonia, potentially generated during infection by urease and other enzymes, enhance VacA toxicity by inhibiting toxin degradation.
Copyright © 2019 American Society for Microbiology.
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14 MeSH Terms
Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells.
Horvat A, Noto JM, Ramatchandirin B, Zaika E, Palrasu M, Wei J, Schneider BG, El-Rifai W, Peek RM, Zaika AI
(2018) Oncogene 37: 5054-5065
MeSH Terms: Antigens, Bacterial, Autophagy, Bacterial Proteins, Cell Line, Tumor, Down-Regulation, Epithelial Cells, Gastric Mucosa, HCT116 Cells, Helicobacter Infections, Helicobacter pylori, Humans, Signal Transduction, Stomach, Stomach Neoplasms, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Up-Regulation, Virulence Factors
Show Abstract · Added September 25, 2018
Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bacterial virulence factors are complex and interrelated, making it difficult to elucidate specific processes associated with H. pylori-induced tumorigenesis. In this study, we found that H. pylori inhibits p14ARF tumor suppressor by inducing its degradation. This effect was found to be strain-specific. Downregulation of p14ARF induced by H. pylori leads to inhibition of autophagy in a p53-independent manner in infected cells. We identified TRIP12 protein as E3 ubiquitin ligase that is upregulated by H. pylori, inducing ubiquitination and subsequent degradation of p14ARF protein. Using isogenic H. pylori mutants, we found that induction of TRIP12 is mediated by bacterial virulence factor CagA. Increased expression of TRIP12 protein was found in infected gastric epithelial cells in vitro and human gastric mucosa of H. pylori-infected individuals. In conclusion, our data demonstrate a new mechanism of ARF inhibition that may affect host-bacteria interactions and facilitate tumorigenic transformation in the stomach.
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19 MeSH Terms
Manganese and the Insulin-IGF Signaling Network in Huntington's Disease and Other Neurodegenerative Disorders.
Bryan MR, Bowman AB
(2017) Adv Neurobiol 18: 113-142
MeSH Terms: Alzheimer Disease, Amyotrophic Lateral Sclerosis, Animals, Autophagy, Brain, Disease Models, Animal, Humans, Huntingtin Protein, Huntington Disease, Insulin, Manganese, Mitochondria, Neostriatum, Neural Stem Cells, Neurodegenerative Diseases, Parkinson Disease, Reactive Oxygen Species, Signal Transduction, Somatomedins
Show Abstract · Added April 11, 2018
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn-demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions.
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Shear stress induces noncanonical autophagy in intestinal epithelial monolayers.
Kim SW, Ehrman J, Ahn MR, Kondo J, Lopez AAM, Oh YS, Kim XH, Crawley SW, Goldenring JR, Tyska MJ, Rericha EC, Lau KS
(2017) Mol Biol Cell 28: 3043-3056
MeSH Terms: Actins, Autophagy, Caco-2 Cells, Cell Culture Techniques, Epithelium, Humans, Intestinal Mucosa, Intestines, Microvilli, Stress, Physiological, Vacuoles
Show Abstract · Added April 3, 2018
Flow of fluids through the gut, such as milk from a neonatal diet, generates a shear stress on the unilaminar epithelium lining the lumen. We report that exposure to physiological levels of fluid shear stress leads to the formation of large vacuoles, containing extracellular contents within polarizing intestinal epithelial cell monolayers. These observations lead to two questions: how can cells lacking primary cilia transduce shear stress, and what molecular pathways support the formation of vacuoles that can exceed 80% of the cell volume? We find that shear forces are sensed by actin-rich microvilli that eventually generate the apical brush border, providing evidence that these structures possess mechanosensing ability. Importantly, we identified the molecular pathway that regulates large vacuole formation downstream from mechanostimulation to involve central components of the autophagy pathway, including ATG5 and LC3, but not Beclin. Together our results establish a novel link between the actin-rich microvilli, the macroscopic transport of fluids across cells, and the noncanonical autophagy pathway in organized epithelial monolayers.
© 2017 Kim et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8α dendritic cells.
Parekh VV, Pabbisetty SK, Wu L, Sebzda E, Martinez J, Zhang J, Van Kaer L
(2017) Proc Natl Acad Sci U S A 114: E6371-E6380
MeSH Terms: Animals, Antigen Presentation, Autophagy, Autophagy-Related Proteins, CD8 Antigens, CD8-Positive T-Lymphocytes, Cells, Cultured, Class III Phosphatidylinositol 3-Kinases, Cross-Priming, Cytokines, Dendritic Cells, Endocytosis, Histocompatibility Antigens Class I, Melanoma, Experimental, Membrane Proteins, Mice, Mice, Knockout, Phagocytosis
Show Abstract · Added March 26, 2019
The class III PI3K Vacuolar protein sorting 34 (Vps34) plays a role in both canonical and noncanonical autophagy, key processes that control the presentation of antigens by dendritic cells (DCs) to naive T lymphocytes. We generated DC-specific -deficient mice to assess the contribution of Vps34 to DC functions. We found that DCs from these animals have a partially activated phenotype, spontaneously produce cytokines, and exhibit enhanced activity of the classic MHC class I and class II antigen-presentation pathways. Surprisingly, these animals displayed a defect in the homeostatic maintenance of splenic CD8α DCs and in the capacity of these cells to cross-present cell corpse-associated antigens to MHC class I-restricted T cells, a property that was associated with defective expression of the T-cell Ig mucin (TIM)-4 receptor. Importantly, mice deficient in the Vps34-associated protein Rubicon, which is critical for a noncanonical form of autophagy called "Light-chain 3 (LC3)-associated phagocytosis" (LAP), lacked such defects. Finally, consistent with their defect in the cross-presentation of apoptotic cells, DC-specific -deficient animals developed increased metastases in response to challenge with B16 melanoma cells. Collectively, our studies have revealed a critical role of Vps34 in the regulation of CD8α DC homeostasis and in the capacity of these cells to process and present antigens associated with apoptotic cells to MHC class I-restricted T cells. Our findings also have important implications for the development of small-molecule inhibitors of Vps34 for therapeutic purposes.
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Prominin-1 Is a Novel Regulator of Autophagy in the Human Retinal Pigment Epithelium.
Bhattacharya S, Yin J, Winborn CS, Zhang Q, Yue J, Chaum E
(2017) Invest Ophthalmol Vis Sci 58: 2366-2387
MeSH Terms: AC133 Antigen, Adult, Aged, Animals, Autophagy, Blotting, Western, Cells, Cultured, Female, Flow Cytometry, Gene Expression Regulation, Humans, Immunoprecipitation, Macular Degeneration, Male, Microscopy, Confocal, Middle Aged, RNA, Rabbits, Real-Time Polymerase Chain Reaction, Retinal Pigment Epithelium, Signal Transduction, Young Adult
Show Abstract · Added June 11, 2018
Purpose - Prominin-1 (Prom1) is a transmembrane glycoprotein, which is expressed in stem cell lineages, and has recently been implicated in cancer stem cell survival. Mutations in the Prom1 gene have been shown to disrupt photoreceptor disk morphogenesis and cause an autosomal dominant form of Stargardt-like macular dystrophy (STGD4). Despite the apparent structural role of Prom1 in photoreceptors, its role in other cells of the retina is unknown. The purpose of this study is to investigate the role of Prom1 in the highly metabolically active cells of the retinal pigment epithelium (RPE).
Methods - Lentiviral siRNA and the genome editing CRISPR/Cas9 system were used to knockout Prom1 in primary RPE and ARPE-19 cells, respectively. Western blotting, confocal microscopy, and flow sight imaging cytometry assays were used to quantify autophagy flux. Immunoprecipitation was used to detect Prom1 interacting proteins.
Results - Our studies demonstrate that Prom1 is primarily a cytosolic protein in the RPE. Stress signals and physiological aging robustly increase autophagy with concomitant upregulation of Prom1 expression. Knockout of Prom1 increased mTORC1 and mTORC2 signaling, decreased autophagosome trafficking to the lysosome, increased p62 accumulation, and inhibited autophagic puncta induced by activators of autophagy. Conversely, ectopic overexpression of Prom1 inhibited mTORC1 and mTORC2 activities, and potentiated autophagy flux. Through interactions with p62 and HDAC6, Prom1 regulates autophagosome maturation and trafficking, suggesting a new cytoplasmic role of Prom1 in RPE function.
Conclusions - Our results demonstrate that Prom1 plays a key role in the regulation of autophagy via upstream suppression of mTOR signaling and also acting as a component of a macromolecular scaffold involving p62 and HDAC6.
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Reactive gamma-ketoaldehydes as novel activators of hepatic stellate cells in vitro.
Longato L, Andreola F, Davies SS, Roberts JL, Fusai G, Pinzani M, Moore K, Rombouts K
(2017) Free Radic Biol Med 102: 162-173
MeSH Terms: Aldehydes, Apoptosis, Autophagy, Cell Proliferation, Hepatic Stellate Cells, Humans, Lipid Peroxidation, Liver, Liver Cirrhosis, NF-kappa B, Oxidative Stress, Prostaglandins E, Reactive Oxygen Species
Show Abstract · Added July 17, 2019
AIMS - Products of lipid oxidation, such as 4-hydroxynonenal (4-HNE), are key activators of hepatic stellate cells (HSC) to a pro-fibrogenic phenotype. Isolevuglandins (IsoLG) are a family of acyclic γ-ketoaldehydes formed through oxidation of arachidonic acid or as by-products of the cyclooxygenase pathway. IsoLGs are highly reactive aldehydes which are efficient at forming protein adducts and cross-links at concentrations 100-fold lower than 4-hydroxynonenal. Since the contribution of IsoLGs to liver injury has not been studied, we synthesized 15-E-IsoLG and used it to investigate whether IsoLG could induce activation of HSC.
RESULTS - Primary human HSC were exposed to 15-E-IsoLG for up to 48h. Exposure to 5μM 15-E-IsoLG in HSCs promoted cytotoxicity and apoptosis. At non-cytotoxic doses (50 pM-500nM) 15-E-IsoLG promoted HSC activation, indicated by increased expression of α-SMA, sustained activation of ERK and JNK signaling pathways, and increased mRNA and/or protein expression of cytokines and chemokines, which was blocked by inhibitors of JNK and NF-kB. In addition, IsoLG promoted formation of reactive oxygen species, and induced an early activation of ER stress, followed by autophagy. Inhibition of autophagy partially reduced the pro-inflammatory effects of IsoLG, suggesting that it might serve as a cytoprotective response.
INNOVATION - This study is the first to describe the biological effects of IsoLG in primary HSC, the main drivers of hepatic fibrosis.
CONCLUSIONS - IsoLGs represent a newly identified class of activators of HSC in vitro, which are biologically active at concentrations as low as 500 pM, and are particularly effective at promoting a pro-inflammatory response and autophagy.
Copyright © 2016. Published by Elsevier Inc.
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Telomerase, Autophagy and Acute Kidney Injury.
Harris RC, Cheng H
(2016) Nephron 134: 145-148
MeSH Terms: Acute Kidney Injury, Autophagy, Humans, Telomerase, Telomere
Show Abstract · Added April 26, 2017
In humans, aging is associated with telomere shortening and increased susceptibility to acute kidney injury. Telomerase is essential to maintain telomere length. The fourth generation mice with telomerase deletion have progressive shortening of telomeres. Those mice delayed recovery from ischemia-reperfusion injury, due to an increase in tubule cell senescence and impairment of autophagy, the latter of which may be mediated in part by increased mTOR signaling. © 2016 S. Karger AG, Basel.
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5 MeSH Terms
Insect immunology and hematopoiesis.
Hillyer JF
(2016) Dev Comp Immunol 58: 102-18
MeSH Terms: Animals, Apoptosis, Autophagy, Hematopoiesis, Hemocytes, Host-Pathogen Interactions, Immunity, Innate, Insect Proteins, Insect Viruses, Insecta, Phagocytosis, Receptors, Pattern Recognition
Show Abstract · Added February 5, 2016
Insects combat infection by mounting powerful immune responses that are mediated by hemocytes, the fat body, the midgut, the salivary glands and other tissues. Foreign organisms that have entered the body of an insect are recognized by the immune system when pathogen-associated molecular patterns bind host-derived pattern recognition receptors. This, in turn, activates immune signaling pathways that amplify the immune response, induce the production of factors with antimicrobial activity, and activate effector pathways. Among the immune signaling pathways are the Toll, Imd, Jak/Stat, JNK, and insulin pathways. Activation of these and other pathways leads to pathogen killing via phagocytosis, melanization, cellular encapsulation, nodulation, lysis, RNAi-mediated virus destruction, autophagy and apoptosis. This review details these and other aspects of immunity in insects, and discusses how the immune and circulatory systems have co-adapted to combat infection, how hemocyte replication and differentiation takes place (hematopoiesis), how an infection prepares an insect for a subsequent infection (immune priming), how environmental factors such as temperature and the age of the insect impact the immune response, and how social immunity protects entire groups. Finally, this review highlights some underexplored areas in the field of insect immunobiology.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers.
Young CD, Arteaga CL, Cook RS
(2015) Breast Cancer Res 17: 148
MeSH Terms: Apoptosis, Autophagy, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, Humans, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Receptor, ErbB-2, Signal Transduction
Show Abstract · Added April 15, 2019
INTRODUCTION - Human epidermal growth factor receptor-2 (HER2) gene amplification (HER2+) drives tumor cell growth and survival in ~25% of breast cancers. HER2 signaling activates the type I phosphoinositide 3-kinase (PI3K), upon which these tumors rely. Consequently, inhibitors of HER2 and type I PI3K block growth and increase apoptosis in HER2+ breast cancers, especially when used in combination. However, the impact of type III PI3K inhibition, particularly in combination with HER2 blockade or type I PI3K inhibition, remains less clear.
METHODS - We utilized small molecule kinase inhibitors, locked nucleic acid antisense oligonucleotides (LNA-ASOs), and siRNA to assess proliferation, autophagy, apoptosis, and protein expression in cell culture models of HER2+ breast cancers.
RESULTS - Treatment of HER2+ breast cancer cells with HER2 inhibitors or type I PI3K kinase inhibitors, alone or in combination, blocked type I PI3K signaling, reduced tumor cell growth, and induced autophagy. Knockdown of the type I PI3K, p110α, using an LNA-ASO termed EZN4150 inhibited PI3K-mediated Akt phosphorylation. However, in contrast to catalytic inhibitors of type I PI3Ks, EZN4150 did not induce autophagy, and blocked autophagy in response to inhibitors of HER2 or type I PI3Ks in a dominant fashion. Sequence analysis of EZN4150 revealed significant homology to the gene encoding the type III PI3K, Vps34, a key component for autophagy induction. EZN4150 simultaneously reduced expression of both p110α and Vps34. Combined inhibition of PI3K signaling and autophagy using individual siRNAs against p110α and Vps34 or using pharmacological type I and type III PI3K inhibitors recapitulated what was seen with EZN4150, and robustly enhanced tumor cell killing.
CONCLUSIONS - These studies highlight the important role of Vps34-mediated autophagy in limiting the anti-tumor response to inhibitors of HER2 or type I PI3K in HER2+ breast cancers. The type III PI3K Vps34 represents a potential therapeutic target to block treatment-induced autophagy and enhance tumor cell killing.
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