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Shashank Rai, Maryam Arasteh, Matthew Jefferson, Timothy Pearson, Yingxue Wang, Weijiao Zhang, Bertalan Bicsak, Devina Divekar, Penny P Powell, Ronald Nauman, Naiara Beraza, Simon R Carding, Oliver Florey, Ulrike Mayer, Thomas Wileman
Macroautophagy/autophagy delivers damaged proteins and organelles to lysosomes for degradation, and plays important roles in maintaining tissue homeostasis by reducing tissue damage. The translocation of LC3 to the limiting membrane of the phagophore, the precursor to the autophagosome, during autophagy provides a binding site for autophagy cargoes, and facilitates fusion with lysosomes. An autophagy-related pathway called LC3-associated phagocytosis (LAP) targets LC3 to phagosome and endosome membranes during uptake of bacterial and fungal pathogens, and targets LC3 to swollen endosomes containing particulate material or apoptotic cells...
November 7, 2018: Autophagy
Zhen Yang, Qi Sun, Junfei Guo, Shixing Wang, Ge Song, Weiying Liu, Min Liu, Hua Tang
Emerging evidence has revealed that miRNAs could upregulate the expression levels of target genes. However, the molecular mechanism underlying upregulation of targets mediated by miRNAs remains unclear. In this study, we found a novel miRNA named MIR-G-1 by GRSF1-RNA immunoprecipitation (RIP)-deep sequencing, which could directly target and upregulate LMNB1 and TMED5 in a GRSF1-dependent manner in cervical cancer cells. In addition, upregulated MIR-G-1 in cervical cancer promoted a malignant phenotype in vitro and in vivo...
November 5, 2018: Autophagy
Jingyue Jia, Yakubu Princely Abudu, Aurore Claude-Taupin, Yuexi Gu, Suresh Kumar, Seong Won Choi, Ryan Peters, Michal H Mudd, Lee Allers, Michelle Salemi, Brett Phinney, Terje Johansen, Vojo Deretic
The Ser/Thr protein kinase MTOR (mechanistic target of rapamycin kinase) regulates cellular metabolism and controls macroautophagy/autophagy. Autophagy has both metabolic and quality control functions, including recycling nutrients at times of starvation and removing dysfunctional intracellular organelles. Lysosomal damage is one of the strongest inducers of autophagy, and yet mechanisms of its activation in response to lysosomal membrane damage are not fully understood. Our recent study has uncovered a new signal transduction system based on cytosolic galectins that elicits autophagy by controlling master regulators of metabolism and autophagy, MTOR and AMPK, in response to lysosomal damage...
November 5, 2018: Autophagy
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October 29, 2018: Autophagy
Federico Pietrocola, Francesca Castoldi, Oliver Kepp, Didac Carmona-Gutierrez, Frank Madeo, Guido Kroemer
A recent prospective epidemiological study suggested that an increase in the nutritional uptake of the natural polyamine spermidine is associated with reduced overall and cancer-specific mortality. Here, we speculate through which mechanisms spermidine might exert such oncopreventive effects. Abbreviations: ACLY, ATP citrate lyase; ATG, autophagy-related gene; CoA, coenzyme A; NSCLC, non-small cell lung cancer.
October 24, 2018: Autophagy
Elizabeth Delorme-Axford, Daniel J Klionsky
Incidences of congenital syndrome associated with maternal zika virus (ZIKV) infection during pregnancy are well documented; however, the cellular and molecular mechanisms by which ZIKV infection causes these devastating fetal pathologies are still under active investigation. ZIKV is a member of the flavivirus family and is mainly transmitted to human hosts through Aedes mosquito vectors. However, in vivo models for the neurological tropism of the virus and the arthropod vector have been lacking. A recent study published in Cell Host & Microbe from Dr...
October 24, 2018: Autophagy
Jingyu Yao, Yaoyan Qiu, Lin Jia, David N Zacks
We describe a protocol for rapid and efficient enrichment of autophagosomes from various tissues of the GFP-LC3 mouse. In order to increase the number of autophagosomes, we block autophagy flux in the GFP-LC3 mouse tissue with a single intraperitoneal injection of leupeptin 4-5 h before tissue harvesting. We homogenize dissected tissue samples using a Dounce homogenizer followed by passing the slurry through needles of different sizes to dissociate the cells and disrupt their outer membranes. The post-nuclear supernatant fraction of the cell lysate is further centrifuged and the supernatant fraction is discarded to remove residual cytosolic GFP-LC3 that is not associated with autophagosomes...
October 24, 2018: Autophagy
Ulises Ahumada-Castro, Eduardo Silva-Pavez, Alenka Lovy, Evelyn Pardo, Jordi Molgo, César Cárdenas
The interruption of endoplasmic reticulum (ER)-mitochondrial Ca2+ communication induces a bioenergetic crisis characterized by an increase of MTOR-independent AMPK-dependent macroautophagic/autophagic flux, which is not sufficient to reestablish the metabolic and energetic homeostasis in cancer cells. Here, we propose that upon ER-mitochondrial Ca2+ transfer inhibition, AMPK present at the mitochondria-associated membranes (MAMs) activates localized autophagy via BECN1 (beclin 1). This local response could prevent the proper interorganelle communication that would allow the autophagy-derived metabolites to reach the necessary anabolic pathways to maintain mitochondrial function and cellular homeostasis...
October 23, 2018: Autophagy
Marzia Raimondi, Daniela Cesselli, Carla Di Loreto, Francesco La Marra, Claudio Schneider, Francesca Demarchi
ULK1 (unc-51 like autophagy activating kinase 1) is a core component at multiple steps of canonical macroautophagy/autophagy. The activity of ULK1 is tightly regulated by several post-translational modifications, including ubiquitination, yet the deubiquitinase (DUB) responsible for its reversible deubiquitination has not been described. Here, we identified USP1 (ubiquitin specific peptidase 1) as a key player in the modulation of ULK1 K63-linked deubiquitination. Moreover, both USP1 depletion and its chemical inhibition by pimozide are coupled to a reduction of ULK1 in Triton X-100 soluble cellular lysates, and its compartmentalization to a fraction that can be solubilized in 5 M urea...
October 18, 2018: Autophagy
Paola Rusmini, Katia Cortese, Valeria Crippa, Riccardo Cristofani, Maria Elena Cicardi, Veronica Ferrari, Giulia Vezzoli, Barbara Tedesco, Marco Meroni, Elio Messi, Margherita Piccolella, Mariarita Galbiati, Massimiliano Garrè, Elena Morelli, Thomas Vaccari, Angelo Poletti
Macroautophagy/autophagy, a defense mechanism against aberrant stresses, in neurons counteracts aggregate-prone misfolded protein toxicity. Autophagy induction might be beneficial in neurodegenerative diseases (NDs). The natural compound trehalose promotes autophagy via TFEB (transcription factor EB), ameliorating disease phenotype in multiple ND models, but its mechanism is still obscure. We demonstrated that trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization (LMP)...
October 18, 2018: Autophagy
Caihong Wang, Kyle A Bauckman, Adam S B Ross, Jane W Symington, Marianne M Ligon, Gael Scholtes, Akhil Kumar, Hao-Wei Chang, Joy Twentyman, Bisiayo E Fashemi, Ramnik J Xavier, Indira U Mysorekar
50% of Caucasians carry a Thr300Ala variant (T300A) in the protein encoded by the macroautophagy/autophagy gene ATG16L1. Here, we show that the T300A variant confers protection against urinary tract infections (UTIs), the most common infectious disease in women. Using knockin mice carrying the human T300A variant, we show that the variant limits the UTI-causing bacteria, uropathogenic Escherichia coli (UPEC), from establishing persistent intracellular reservoirs, which can seed UTI recurrence. This phenotype is recapitulated in mice lacking Atg16l1 or Atg7 exclusively in the urothelium...
October 18, 2018: Autophagy
M S Gilardini Montani, R Santarelli, M Granato, R Gonnella, M R Torrisi, A Faggioni, M Cirone
EBV has been reported to impair monocyte in vitro differentiation into dendritic cells (DCs) and reduce cell survival. In this study, we added another layer of knowledge to this topic and showed that these effects correlated with macroautophagy/autophagy, ROS and mitochondrial biogenesis reduction. Of note, autophagy and ROS, although strongly interconnected, have been separately reported to be induced by CSF2/GM-CSF (colony stimulating factor 2) and required for CSF2-IL4-driven monocyte in vitro differentiation into DCs...
October 16, 2018: Autophagy
Huifeng Pi, Min Li, Lingyun Zou, Min Yang, Ping Deng, Tengfei Fan, Menyu Liu, Li Tian, Manyu Tu, Jia Xie, Mengyan Chen, Huijuan Li, Yu Xi, Lei Zhang, Mindi He, Yonghui Lu, Chunhai Chen, Tao Zhang, Zheng Wang, Zhengping Yu, Feng Gao, Zhou Zhou
Cadmium (Cd) is a toxic metal that is widely found in numerous environmental matrices and induces serious adverse effects in various organs and tissues. Bone tissue seems to be a crucial target of Cd contamination. Macroautophagy/autophagy has been proposed to play a pivotal role in Cd-mediated bone toxicity. However, the mechanisms that underlie Cd-induced autophagy are not yet completely understood. We demonstrated that Cd treatment increased autophagic flux and inhibition of the autophagic process using Atg7 gene silencing blocked the Cd-induced mesenchymal stem cell death...
October 16, 2018: Autophagy
Hongyu Li, Ahrom Ham, Thong Chi Ma, Sheng-Han Kuo, Ellen Kanter, Donghoon Kim, Han Seok Ko, Yi Quan, Sergio Pablo Sardi, Aiqun Li, Ottavio Arancio, Un Jung Kang, David Sulzer, Guomei Tang
Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in GbaL444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy...
October 12, 2018: Autophagy
Frank Madeo, Maria A Bauer, Didac Carmona-Gutierrez, Guido Kroemer
Spermidine is a natural polyamine that stimulates cytoprotective macroautophagy/autophagy. External supplementation of spermidine extends lifespan and health span across species, including in yeast, nematodes, flies and mice. In humans, spermidine levels decline with aging, and a possible connection between reduced endogenous spermidine concentrations and age-related deterioration has been suggested. Recent epidemiological data support this notion, showing that an increased uptake of this polyamine with spermidine-rich food diminishes overall mortality associated with cardiovascular diseases and cancer...
October 11, 2018: Autophagy
Yueyang Liu, Xue Xue, Haotian Zhang, Xiaohang Che, Jing Luo, Ping Wang, Jiaoyan Xu, Zheng Xing, Linlin Yuan, Yinglu Liu, Xiaoxiao Fu, Dongmei Su, Shibo Sun, Haonan Zhang, Chunfu Wu, Jingyu Yang
Mounting attention has been focused on defects in macroautophagy/autophagy and the autophagy-lysosomal pathway (ALP) in cerebral ischemia. TFEB (transcription factor EB)-mediated induction of ALP has been recently considered as the common mechanism in ameliorating the pathological lesion of myocardial ischemia and neurodegenerative diseases. Here we explored the vital role of TFEB in permanent middle cerebral artery occlusion (pMCAO)-mediated dysfunction of ALP and ischemic insult in rats. The results showed that ALP function was first enhanced in the early stage of the ischemic process, especially in neurons of the cortex, and this was accompanied by increased TFEB expression and translocation to the nucleus, which was mediated at least in part through activation by PPP3/calcineurin...
October 10, 2018: Autophagy
Clea Bárcena, Carlos López-Otín, Guido Kroemer
Methionine restriction, i.e., a partial depletion of the essential sulfur amino acid methionine from nutrition, extends lifespan in model organisms including yeast, nematodes, mice and rats. Recent results indicate that this strategy also prolongs health span and longevity in 2 short-lived strains of mice (with the LmnaG609G/G609G or zmpste24-/- genotypes) that represent animal models of Hutchinson-Gilford progeria syndrome (HGPS). The beneficial effects of methionine restriction on HGPS could be linked to reduced inflammation, and improved DNA stability, as well as the normalization of lipid and bile acid metabolism...
October 10, 2018: Autophagy
Tania Catarina Medeiros, Martin Graef
Derived from bacterial ancestors, mitochondria have maintained their own albeit strongly reduced genome, mitochondrial DNA (mtDNA), which encodes for a small and highly specialized set of genes. MtDNA exists in tens to thousands of copies packaged in numerous nucleoprotein complexes, termed nucleoids, distributed throughout the dynamic mitochondrial network. Our understanding of the mechanisms of how cells regulate the copy number of mitochondrial genomes has been limited. Here, we summarize and discuss our recent findings that Mip1/POLG (mitochondrial DNA polymerase gamma) critically controls mtDNA copy number by operating in 2 opposing modes, synthesis and, unexpectedly, degradation of mtDNA, when yeast cells face nutrient starvation...
October 10, 2018: Autophagy
Hallvard L Olsvik, Steingrim Svenning, Yakubu Princely Abudu, Andreas Brech, Harald Stenmark, Terje Johansen, Jakob Mejlvang
Starvation is a fundamental type of stress naturally occurring in biological systems. All organisms have therefore evolved different safeguard mechanisms to cope with deficiencies in various types of nutrients. Cells, from yeast to humans, typically respond to amino acid starvation by initiating degradation of cellular components by inducing autophagy. This degradation releases metabolic building blocks to sustain essential core cellular processes. Increasing evidence indicates that starvation-induced autophagy also acts to prepare cells for prolonged starvation by degrading key regulators of different cellular processes...
October 8, 2018: Autophagy
Deniz Gulfem Ozturk, Muhammed Kocak, Arzu Akcay, Kubilay Kinoglu, Erdogan Kara, Yalcin Buyuk, Hilal Kazan, Devrim Gozuacik
Macroautophagy (autophagy) is an evolutionarily conserved recycling and stress response mechanism. Active at basal levels in eukaryotes, autophagy is upregulated under stress providing cells with building blocks such as amino acids. A lysosome-integrated sensor system composed of RRAG GTPases and MTOR complex 1 (MTORC1) regulates lysosome biogenesis and autophagy in response to amino acid availability. Stress-mediated inhibition of MTORC1 results in the dephosphorylation and nuclear translocation of the TFE/MITF family of transcriptional factors, and triggers an autophagy- and lysosomal-related gene transcription program...
October 5, 2018: Autophagy
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