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https://www.readbyqxmd.com/read/29048433/tmem74-promotes-tumor-cell-survival-by-inducing-autophagy-via-interactions-with-atg16l1-and-atg9a
#1
Yizhe Sun, Yingyu Chen, Jingyu Zhang, Lulu Cao, Minwei He, Xi Liu, Ning Zhao, Ang Yin, He Huang, Lu Wang
Autophagy is a highly inducible system of intracellular degradation that occurs in lysosomes or vacuoles. Transmembrane 74 (TMEM74) has been shown to induce autophagy. However, the mechanism by which TMEM74 stimulates autophagy and the impacts of TMEM74-induced autophagy on tumor cell survival remain unclear. In this study, TMEM74 was shown to increase the autophagic flux process in different tumor cell lines. Further investigations revealed that TMEM74 interacts with ATG16L1 and ATG9A. Moreover, distinctive from the common autophagy models, it is found that TMEM74-related autophagy is independent of BECN1/PI3KC3 complex and ULK1, and TMEM74 may initiate and promote autophagy directly via interactions with ATG16L1 and ATG9A responsible for the nucleation and elongation respectively...
August 31, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29036202/toxoplasma-gondii-induces-fak-src-stat3-signaling-during-infection-of-host-cells-that-prevents-parasite-targeting-by-autophagy
#2
Jose-Andres C Portillo, Luis Muniz-Feliciano, Yalitza Lopez Corcino, So Jung Lee, Jennifer Van Grol, Sarah J Parsons, William P Schiemman, Carlos S Subauste
Targeting of Toxoplasma gondii by autophagy is an effective mechanism by which host cells kill the protozoan. Thus, the parasite must avoid autophagic targeting to survive. Here we show that the mammalian cytoplasmic molecule Focal Adhesion Kinase (FAK) becomes activated during invasion of host cells. Activated FAK appears to accompany the formation of the moving junction (as assessed by expression the parasite protein RON4). FAK activation was inhibited by approaches that impaired β1 and β3 integrin signaling...
October 16, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29029244/elmo1-regulates-the-induction-of-autophagy-and-bacterial-clearance-during-enteric-infection
#3
Arup Sarkar, Courtney Tindle, Rama F Pranadinata, Sharon Reed, Lars Eckmann, Thaddeus S Stappenbeck, Peter B Ernst, Soumita Das
Macrophages are specialized phagocytic cells involved in clearing invading pathogens. Earlier we reported the Engulfment and Cell Motility protein 1 (ELMO1) in macrophages mediates bacterial internalization and intestinal inflammation. Here we studied the role of ELMO1 in the fate of internalized target. ELMO1 is present in the intracellular vesicles and enhanced LC3B accumulation following engulfment of Salmonella or treatment with autophagy-inducing rapamycin. ATG5 and ULK1 are involved in classical autophagy while LC3-associated phagocytosis (LAP) is ULK1-independent...
October 5, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28980854/pik3c3-vps34-control-by-acetylation
#4
Hua Su, Wei Liu
PIK3C3/VPS34 (phosphatidylinositol 3-kinase catalytic subunit type 3) converts phosphatidylinositol (PtdIns) to phosphatidylinositol-3-phosphate (PtdIns3P), sustaining macroautophagy/autophagy and endosomal transport. So far, facilitating the assembly of the PIK3C3/VPS34-BECN1-PIK3R4/VPS15/p150 core complex at distinct membranes is the only known way to activate PIK3C3/VPS34 in cells. We have recently revealed a novel mechanism that regulates PIK3C3/VPS34 activation; cellular PIK3C3/VPS34 is repressed under nutrient-rich conditions by EP300/p300-mediated acetylation...
October 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28978086/ampk-activation-dependent-autophagy-compromises-oleanolic-acid-induced-cytotoxicity-in-human-bladder-cancer-cells
#5
Yarong Song, Peng Zhang, Yadong Sun, Xuechao Li, Lifeng Chen, Yajun Xiao, Yifei Xing
Autophagy is an evolutionarily conserved catabolic process in eukaryotic cells, which allows cells to overcome a wide array of of stresses and has recently been shown to result in drug resistance. This study examined the effect of autophagy on oleanolic acid (OA)-induced cytotoxicity against bladder cancer cells. Our study demonstrated that OA inhibited cell viability, proliferation, and induced apoptosis in bladder cancer lines T24 and EJ. Furthermore, OA induced autophagy in both cell lines by activating AMP-activated protein kinase (AMPK), inhibiting mechanistic target of rapamycin (mTOR) and promoting unc-51 like autophagy activating kinase 1 (ULK1)...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28973896/mycobacterium-tuberculosis-is-protected-from-nadph-oxidase-and-lc3-associated-phagocytosis-by-the-lcp-protein-cpsa
#6
Stefan Köster, Sandeep Upadhyay, Pallavi Chandra, Kadamba Papavinasasundaram, Guozhe Yang, Amir Hassan, Steven J Grigsby, Ekansh Mittal, Heidi S Park, Victoria Jones, Fong-Fu Hsu, Mary Jackson, Christopher M Sassetti, Jennifer A Philips
Mycobacterium tuberculosis' success as a pathogen comes from its ability to evade degradation by macrophages. Normally macrophages clear microorganisms that activate pathogen-recognition receptors (PRRs) through a lysosomal-trafficking pathway called "LC3-associated phagocytosis" (LAP). Although Mtuberculosis activates numerous PRRs, for reasons that are poorly understood LAP does not substantially contribute to Mtuberculosis control. LAP depends upon reactive oxygen species (ROS) generated by NADPH oxidase, but Mtuberculosis fails to generate a robust oxidative response...
September 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28924239/the-autophagy-initiator-ulk1-sensitizes-ampk-to-allosteric-drugs
#7
Toby A Dite, Naomi X Y Ling, John W Scott, Ashfaqul Hoque, Sandra Galic, Benjamin L Parker, Kevin R W Ngoei, Christopher G Langendorf, Matthew T O'Brien, Mondira Kundu, Benoit Viollet, Gregory R Steinberg, Kei Sakamoto, Bruce E Kemp, Jonathan S Oakhill
AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for maintaining cellular energy homeostasis. Activation of AMPK by salicylate and the thienopyridone A-769662 is critically dependent on phosphorylation of Ser108 in the β1 regulatory subunit. Here, we show a possible role for Ser108 phosphorylation in cell cycle regulation and promotion of pro-survival pathways in response to energy stress. We identify the autophagy initiator Unc-51-like kinase 1 (ULK1) as a β1-Ser108 kinase in cells...
September 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28923415/diindolylmethane-and-its-halogenated-derivatives-induce-protective-autophagy-in-human-prostate-cancer-cells-via-induction-of-the-oncogenic-protein-aeg-1-and-activation-of-amp-activated-protein-kinase-ampk
#8
Hossam Draz, Alexander A Goldberg, Vladimir I Titorenko, Emma S Tomlinson Guns, Stephen H Safe, J Thomas Sanderson
3,3'-Diindolylmethane (DIM) and its synthetic halogenated derivatives 4,4'-Br2- and 7,7'-Cl2DIM (ring-DIMs) have recently been shown to induce protective autophagy in human prostate cancer cells. The mechanisms by which DIM and ring-DIMs induce autophagy have not been elucidated. As DIM is a mitochondrial ATP-synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of intracellular AMP/ATP ratios and activation of AMP-activated protein kinase (AMPK) signaling in prostate cancer cells...
September 18, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28916822/ampk-phosphorylation-of-ulk1-is-required-for-targeting-of-mitochondria-to-lysosomes-in-exercise-induced-mitophagy
#9
Rhianna C Laker, Joshua C Drake, Rebecca J Wilson, Vitor A Lira, Bevan M Lewellen, Karen A Ryall, Carleigh C Fisher, Mei Zhang, Jeffrey J Saucerman, Laurie J Goodyear, Mondira Kundu, Zhen Yan
Mitochondrial health is critical for skeletal muscle function and is improved by exercise training through both mitochondrial biogenesis and removal of damaged/dysfunctional mitochondria via mitophagy. The mechanisms underlying exercise-induced mitophagy have not been fully elucidated. Here, we show that acute treadmill running in mice causes mitochondrial oxidative stress at 3-12 h and mitophagy at 6 h post-exercise in skeletal muscle. These changes were monitored using a novel fluorescent reporter gene, pMitoTimer, that allows assessment of mitochondrial oxidative stress and mitophagy in vivo, and were preceded by increased phosphorylation of AMP activated protein kinase (Ampk) at tyrosine 172 and of unc-51 like autophagy activating kinase 1 (Ulk1) at serine 555...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28915569/gabarapl1-tumor-suppressive-function-is-independent-of-its-conjugation-to-autophagosomes-in-mcf-7-breast-cancer-cells
#10
Laura Poillet-Perez, Marine Jacquet, Eric Hervouet, Thierry Gauthier, Annick Fraichard, Christophe Borg, Jean-René Pallandre, Bruno J Gonzalez, Yasmina Ramdani, Michaël Boyer-Guittaut, Régis Delage-Mourroux, Gilles Despouy
The GABARAPL1 protein belongs to the ATG8 family whose members are involved in autophagy. Our laboratory previously demonstrated that GABARAPL1 associates with autophagic vesicles, regulates autophagic flux and acts as a tumor suppressor protein in breast cancer. In this study, we aimed to determine whether GABARAPL1 conjugation to autophagosomes is necessary for its tumor suppressive functions using the MCF-7 breast cancer cell line overexpressing GABARAPL1 or a G116A mutant, which is unable to be lipidated and associated to autophagosomes...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28905115/clinical-application-of-snp-array-analysis-in-fetuses-with-ventricular-septal-defects-and-normal-karyotypes
#11
Fang Fu, Qiong Deng, Ting-Ying Lei, Ru Li, Xiang-Yi Jing, Xin Yang, Can Liao
PURPOSE: The present study aims to evaluate the utility of high-resolution single-nucleotide polymorphism (SNP) arrays in fetuses with ventricular septal defects (VSDs) with or without other structural anomalies but with normal karyotypes and to investigate the outcomes of cases of prenatal VSDs via clinical follow-up. METHODS: We analyzed 144 fetuses with VSDs and normal karyotypes using Affymetrix CytoScan HD arrays and the analyses were carried out a year after birth...
September 13, 2017: Archives of Gynecology and Obstetrics
https://www.readbyqxmd.com/read/28890335/the-er-localized-transmembrane-protein-epg-3-vmp1-regulates-serca-activity-to-control-er-isolation-membrane-contacts-for-autophagosome-formation
#12
Yan G Zhao, Yong Chen, Guangyan Miao, Hongyu Zhao, Wenyan Qu, Dongfang Li, Zheng Wang, Nan Liu, Lin Li, She Chen, Pingsheng Liu, Du Feng, Hong Zhang
During autophagosome formation in mammalian cells, isolation membranes (IMs; autophagosome precursors) dynamically contact the ER. Here, we demonstrated that the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. Loss of VMP1 causes stable association of IMs with the ER, thus blocking autophagosome formation. Interaction of WIPI2 with the ULK1/FIP200 complex and PI(3)P contributes to the formation of ER-IM contacts, and these interactions are enhanced by VMP1 depletion. VMP1 controls contact formation by promoting SERCA (sarco[endo]plasmic reticulum calcium ATPase) activity...
September 21, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28877469/autophagy-independent-lysosomal-targeting-regulated-by-ulk1-2-fip200-and-atg9
#13
Jonathan M Goodwin, William E Dowdle, Rowena DeJesus, Zuncai Wang, Philip Bergman, Marek Kobylarz, Alicia Lindeman, Ramnik J Xavier, Gregory McAllister, Beat Nyfeler, Gregory Hoffman, Leon O Murphy
Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that ferritin and its binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a form of selective autophagy. By using genome-scale functional screening, we identify an alternative lysosomal transport pathway for ferritin that requires FIP200, ATG9A, VPS34, and TAX1BP1 but lacks involvement of the ATG8 lipidation machinery that constitutes classical macroautophagy...
September 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28860574/involvement-of-mtor-autophagy-in-the-selection-of-primitive-mesenchymal-stem-cells-in-chitosan-film-3-dimensional-culture
#14
Hsiao-Ying Chiu, Yeou-Guang Tsay, Shih-Chieh Hung
Mesenchymal stem cells (MSCs) in conventional monolayer culture are heterogeneous and contain a significant portion of senescent cells. MSCs cultured on chitosan film form 3-dimenional spheres, increase in stemness and differentiation capability; however, the underlying mechanisms remain elusive. We first demonstrate chitosan film culture induces apoptosis at 2 days, with specificity in late senescent cells. Especially in senescent cells, chitosan film culture activates mTOR, which activates S6K/S6/4E-BP1 to enhance fibronection synthesis and peripheral dead cell attachment, and phosphorylates ULK1 at S757 to further inactivate ULK1, LC3A and autophagy, thereby inducing apoptosis...
August 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28855439/intrauterine-growth-retardation-promotes-fetal-intestinal-autophagy-in-rats-via-the-mechanistic-target-of-rapamycin-pathway
#15
Chao Wang, Ruiming Zhang, Le Zhou, Jintian He, Qiang Huang, Farman A Siyal, Lili Zhang, Xiang Zhong, Tian Wang
Intrauterine growth retardation (IUGR) impairs fetal intestinal development, and is associated with high perinatal morbidity and mortality. However, the mechanism underlying this intestinal injury is largely unknown. We aimed to investigate this mechanism through analysis of intestinal autophagy and related signaling pathways in a rat model of IUGR. Normal weight (NW) and IUGR fetuses were obtained from primiparous rats via ad libitum food intake and 50% food restriction, respectively. Maternal serum parameters, fetal body weight, organ weights, and fetal blood glucose were determined...
August 31, 2017: Journal of Reproduction and Development
https://www.readbyqxmd.com/read/28844862/vps34-acetylation-controls-its-lipid-kinase-activity-and-the-initiation-of-canonical-and-non-canonical-autophagy
#16
Hua Su, Fei Yang, Qiuting Wang, Qiuhong Shen, Jingtao Huang, Chao Peng, Yi Zhang, Wei Wan, Catherine C L Wong, Qiming Sun, Fudi Wang, Tianhua Zhou, Wei Liu
The class III phosphoinositide 3-kinase VPS34 plays a key role in the regulation of vesicular trafficking and macroautophagy. So far, we know little about the molecular mechanism of VPS34 activation besides its interaction with regulatory proteins to form complexes. Here, we report that VPS34 is specifically acetylated by the acetyltransferase p300, and p300-mediated acetylation represses VPS34 activity. Acetylation at K771 directly diminishes the affinity of VPS34 for its substrate PI, while acetylation at K29 hinders the VPS34-Beclin 1 core complex formation...
September 21, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28844109/intratumoral-heterogeneity-of-somatic-mutations-for-nrip1-dok1-ulk1-ulk2-dlgap3-pard3-and-prkci-in-colon-cancers
#17
Eun Ji Choi, Ju Hwa Lee, Min Sung Kim, Sang Yong Song, Nam Jin Yoo, Sug Hyung Lee
Both NRIP1 and DOK1 genes are considered candidate tumor suppressor genes (TSGs). Also, cell polarity-related genes PARD3, PRKCI and DLGAP3, and autophagy-related genes ULK1 and ULK2 genes are considered to play crucial roles in tumorigenesis. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H)...
August 26, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28837807/withdrawn-schisandrin-b-suppresses-nlrp3-inflammasome-activation-to-alleviate-myocardial-ischemia-reperfusion-injury-via-maintaining-mitochondrial-autophagy
#18
Peiyong Zhang, Xiaochen Liu, Guotao Huang, Caiyan Bai, Zhenling Zhang, Hongjun Li
This article has been retracted at the request of the authors. The Editor in Chief has agreed to retract this article and the publisher supports the decision. The authors have indicated that their initial results were not reproducible when conducted by their colleagues. They indicated that the levels of autophagy were significantly different in the MI/R mice model in the respective results. The authors of this article would like to apologize to all affected parties. The full Elsevier Policy on Article Withdrawal can be found at https://www...
August 31, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28837152/lysosomotropism-depends-on-glucose-a-chloroquine-resistance-mechanism
#19
Laura E Gallagher, Ohood A Radhi, Mahmud O Abdullah, Anthony G McCluskey, Marie Boyd, Edmond Y W Chan
There has been long-standing interest in targeting pro-survival autophagy as a combinational cancer therapeutic strategy. Clinical trials are in progress testing chloroquine (CQ) or its derivatives in combination with chemo- or radiotherapy for solid and haematological cancers. Although CQ has shown efficacy in preclinical models, its mechanism of action remains equivocal. Here, we tested how effectively CQ sensitises metastatic breast cancer cells to further stress conditions such as ionising irradiation, doxorubicin, PI3K-Akt inhibition and serum withdrawal...
August 24, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28821708/a-reversible-phospho-switch-mediated-by-ulk1-regulates-the-activity-of-autophagy-protease-atg4b
#20
N Pengo, A Agrotis, K Prak, J Jones, R Ketteler
Upon induction of autophagy, the ubiquitin-like protein LC3 is conjugated to phosphatidylethanolamine (PE) on the inner and outer membrane of autophagosomes to allow cargo selection and autophagosome formation. LC3 undergoes two processing steps, the proteolytic cleavage of pro-LC3 and the de-lipidation of LC3-PE from autophagosomes, both executed by the same cysteine protease ATG4. How ATG4 activity is regulated to co-ordinate these events is currently unknown. Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316...
August 18, 2017: Nature Communications
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