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https://www.readbyqxmd.com/read/29661845/lysosome-enlargement-during-inhibition-of-the-lipid-kinase-pikfyve-proceeds-through-lysosome-coalescence
#1
Christopher H Choy, Golam Saffi, Matthew A Gray, Callen Wallace, Roya M Dayam, Zhen-Yi A Ou, Guy Lenk, Rosa Puertollano, Simon C Watkins, Roberto J Botelho
Lysosomes receive and degrade cargo from endocytosis, phagocytosis and autophagy. They also play an important role in sensing and instructing cells on their metabolic state. The lipid kinase PIKfyve generates phosphatidylinositol-3,5-bisphosphate to modulate lysosome function. PIKfyve inhibition leads to impaired degradative capacity, ion dysregulation, abated autophagic flux, and a massive enlargement of lysosomes. Collectively, this leads to various physiological defects including embryonic lethality, neurodegeneration and overt inflammation...
April 16, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29650965/a-novel-autophagy-enhancer-as-a-therapeutic-agent-against-metabolic-syndrome-and-diabetes
#2
Hyejin Lim, Yu-Mi Lim, Kook Hwan Kim, Young Eui Jeon, Kihyoun Park, Jinyoung Kim, Hui-Yun Hwang, Dong Jin Lee, Haushabhau Pagire, Ho Jeong Kwon, Jin Hee Ahn, Myung-Shik Lee
Autophagy is a critical regulator of cellular homeostasis, dysregulation of which is associated with diverse diseases. Here we show therapeutic effects of a novel autophagy enhancer identified by high-throughput screening of a chemical library against metabolic syndrome. An autophagy enhancer increases LC3-I to LC3-II conversion without mTOR inhibition. MSL, an autophagy enhancer, activates calcineurin, and induces dephosphorylation/nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy gene expression...
April 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29644770/tmem55b-contributes-to-lysosomal-homeostasis-and-amino-acid-induced-mtorc1-activation
#3
Yutaka Hashimoto, Michiko Shirane, Keiichi I Nakayama
Mammalian/mechanistic target of rapamycin complex 1 (mTORC1) responds to growth factors and nutrient availability. Amino acids induce the recruitment of mTORC1 to the lysosomal membrane and its consequent activation, but the molecular mechanism of such activation has remained unclear. We have now examined the role of TMEM55B, a lysosomal protein of unknown molecular function, in this process on the basis of the results of proteomics and immunofluorescence analyses showing that TMEM55B interacts with many proteins that participate in mTORC1 activation including components of the vacuolar-type proton ATPase (V-ATPase) and Ragulator complexes at the lysosomal membrane...
April 11, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/29628303/overexpression-of-tfeb-drives-a-pleiotropic-neurotrophic-effect-and-prevents-parkinson-s-disease-related-neurodegeneration
#4
Albert Torra, Annabelle Parent, Thais Cuadros, Beatriz Rodríguez-Galván, Esther Ruiz-Bronchal, Andrea Ballabio, Analía Bortolozzi, Miquel Vila, Jordi Bové
The possible implication of transcription factor EB (TFEB) as a therapeutic target in Parkinson's disease has gained momentum since it was discovered that TFEB controls lysosomal biogenesis and autophagy and that its activation might counteract lysosomal impairment and protein aggregation. However, the majority of putative direct targets of TFEB described to date is linked to a range of biological processes that are not related to the lysosomal-autophagic system. Here, we assessed the effect of overexpressing TFEB with an adeno-associated viral vector in mouse substantia nigra dopaminergic neurons...
February 27, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29622767/pex5-regulates-autophagy-via-the-mtorc1-tfeb-axis-during-starvation
#5
So Young Eun, Joon No Lee, In-Koo Nam, Zhi-Qiang Liu, Hong-Seob So, Seong-Kyu Choe, RaeKil Park
Defects in the PEX5 gene impair the import of peroxisomal matrix proteins, leading to nonfunctional peroxisomes and other associated pathological defects such as Zellweger syndrome. Although PEX5 regulates autophagy process in a stress condition, the mechanisms controlling autophagy by PEX5 under nutrient deprivation are largely unknown. Herein, we show a novel function of PEX5 in the regulation of autophagy via Transcription Factor EB (TFEB). Under serum-starved conditions, when PEX5 is depleted, the mammalian target of rapamycin (mTORC1) inhibitor TSC2 is downregulated, which results in increased phosphorylation of the mTORC1 substrates, including 70S6K, S6K, and 4E-BP-1...
April 6, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29618792/subcutaneous-ehrlich-ascites-carcinoma-mice-model-for-studying-cancer-induced-cardiomyopathy
#6
Sneha Mishra, Ankit Kumar Tamta, Mohsen Sarikhani, Perumal Arumugam Desingu, Shruti M Kizkekra, Anwit Shriniwas Pandit, Shweta Kumar, Danish Khan, Sathees C Raghavan, Nagalingam R Sundaresan
Cardiomyopathy is one of the characteristic features of cancer. In this study, we establish a suitable model to study breast cancer-induced cardiomyopathy in mice. We used Ehrlich Ascites Carcinoma cells to induce subcutaneous tumor in 129/SvJ mice and studied its effect on heart function. In Ehrlich Ascites Carcinoma bearing mice, we found significant reduction in left ventricle wall thickness, ejection fraction, and fractional shortening increase in left ventricle internal diameter. We found higher muscle atrophy, degeneration, fibrosis, expression of cell-adhesion molecules and cell death in tumor-bearing mice hearts...
April 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29606629/trans-fats-inhibit-autophagy-induced-by-saturated-fatty-acids
#7
Allan Sauvat, Guo Chen, Kevin Müller, Mingming Tong, Fanny Aprahamian, Sylvère Durand, Giulia Cerrato, Lucillia Bezu, Marion Leduc, Joakim Franz, Patrick Rockenfeller, Junichi Sadoshima, Frank Madeo, Oliver Kepp, Guido Kroemer
Depending on the length of their carbon backbone and their saturation status, natural fatty acids have rather distinct biological effects. Thus, longevity of model organisms is increased by extra supply of the most abundant natural cis-unsaturated fatty acid, oleic acid, but not by that of the most abundant saturated fatty acid, palmitic acid. Here, we systematically compared the capacity of different saturated, cis-unsaturated and alien (industrial or ruminant) trans-unsaturated fatty acids to provoke cellular stress in vitro, on cultured human cells expressing a battery of distinct biosensors that detect signs of autophagy, Golgi stress and the unfolded protein response...
March 27, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29600279/intracellular-trafficking-and-persistence-of-acinetobacter-baumannii-requires-transcription-factor-eb
#8
Raquel Parra-Millán, David Guerrero-Gómez, Rafael Ayerbe-Algaba, Maria Eugenia Pachón-Ibáñez, Antonio Miranda-Vizuete, Jerónimo Pachón, Younes Smani
Acinetobacter baumannii is a significant human pathogen associated with hospital-acquired infections. While adhesion, an initial and important step in A. baumannii infection, is well characterized, the intracellular trafficking of this pathogen inside host cells remains poorly studied. Here, we demonstrate that transcription factor EB (TFEB) is activated after A. baumannii infection of human lung epithelial cells (A549). We also show that TFEB is required for the invasion and persistence inside A549 cells...
March 2018: MSphere
https://www.readbyqxmd.com/read/29594326/dysregulation-of-autophagy-in-rat-liver-with-mitochondrial-dna-depletion-induced-by-the-nucleoside-analogue-zidovudine
#9
Ana Santos-Llamas, Maria J Monte, Jose J G Marin, Maria J Perez
The nucleoside reverse transcriptase inhibitor zidovudine (AZT), used in HIV infection treatment, induces mitochondrial DNA (mtDNA) depletion. A cause-effect relationship between mtDNA status alterations and autophagy has been reported. Both events are common in several liver diseases, including hepatocellular carcinoma. Here, we have studied autophagy activation in rat liver with mtDNA depletion induced by AZT administration in drinking water for 35 days. AZT at a concentration of 1 mg/ml, but not 0.5 mg/ml in the drinking water, decreased mtDNA levels in rat liver and extrahepatic tissues...
March 28, 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29570219/advanced-glycation-end-products-suppress-autophagic-flux-in-podocytes-by-activating-mammalian-target-of-rapamycin-and-inhibiting-nuclear-translocation-of-transcription-factor-eb
#10
Xingchen Zhao, Yuanhan Chen, Xiaofan Tan, Li Zhang, Hong Zhang, Zhilian Li, Shuangxin Liu, Ruizhao Li, Ting Lin, Ruyi Liao, Qianmei Zhang, Wei Dong, Wei Shi, Xinling Liang
Insufficient autophagy in podocytes is related to podocyte injury in diabetic nephropathy (DN). Advanced glycation end-products (AGEs) are major factors of podocyte injury in DN. However, the role and mechanism of AGEs on autophagic dysfunction remains unknown. We investigated autophagic flux in AGEs-stimulated cultured podocytes using multiple assays: western blotting, reverse transcription quantitative PCR, immunofluorescence staining and electron microscopy. We also utilized chloroquine and a fluorescent probe to monitor the formation and turnover of autophagosomes...
March 23, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29559387/endurance-exercise-mediates-neuroprotection-against-mptp-mediated-parkinson-s-disease-via-enhanced-neurogenesis-antioxidant-capacity-and-autophagy
#11
Yongchul Jang, Insu Kwon, Wankeun Song, Ludmila M Cosio-Lima, Youngil Lee
Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction. Growing evidence has demonstrated that endurance exercise (EE) confers neuroprotection against PD; However, the exact molecular mechanisms responsible for exercise-induced protection of dopaminergic neurons in PD remain unclear. Since oxidative stress plays a key role in the degenerative process of PD. We investigated whether EE-induced neuroprotection is associated with enhanced antioxidative capacity and autophagy, using a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration...
March 17, 2018: Neuroscience
https://www.readbyqxmd.com/read/29524554/bafilomycin-a1-increases-the-sensitivity-of-tongue-squamous-cell-carcinoma-cells-to-cisplatin-by-inhibiting-the-lysosomal-uptake-of-platinum-ions-but-not-autophagy
#12
Hong-Ying Chu, Xue Chen, Yu-E Jiang, Wei Wang, Xiao Qi, Zhao-Ming Zhong, Mu-Sheng Zeng, Xiao-Feng Zhu, Chuan-Zheng Sun
The role of autophagy in tongue squamous cell carcinoma (TSCC) cisplatin resistance is unclear. We aimed to identify a possible synergistic effect of autophagy inhibitors and cisplatin in TSCC cells and explore the underlying mechanism. Our results indicate that autophagic flux was high in TSCC cells; Autophagy inhibitor bafilomycin A1 increased cisplatin cytotoxicity in TSCC cells by inhibiting lysosomal uptake of platinum and enhancing intracellular platinum ion binding to DNA; Autophagy gene (Atg5) knockout in TSCC cells did not duplicate the above-mentioned sensitization of bafilomycin A1...
March 7, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29523960/taurine-is-an-amino-acid-with-the-ability-to-activate-autophagy-in-adipocytes
#13
Hiroki Kaneko, Masaki Kobayashi, Yuhei Mizunoe, Maho Yoshida, Hiromine Yasukawa, Shunsuke Hoshino, Rei Itagawa, Takuma Furuichi, Naoyuki Okita, Yuka Sudo, Masato Imae, Yoshikazu Higami
Alterations in adipocyte characteristics are highly implicated in the pathology of obesity. In a recent article, we demonstrated that high-fat diet-induced obesity impairs lysosomal function, thereby suppressing autophagy in mice white adipose tissue. Taurine, an amino acid naturally contained in the normal diet and existing ubiquitously in tissues, has been reported to improve insulin resistance and chronic inflammation in animal models, but underlying mechanisms remain unclear. From these findings, we hypothesized that improvement of obese pathology by taurine may be mediated through recovery of autophagy...
March 9, 2018: Amino Acids
https://www.readbyqxmd.com/read/29516164/cathepsin-k-expression-in-clear-cell-sugar-tumor-pecoma-of-the-lung
#14
Anna Caliò, Maria Cecilia Mengoli, Alberto Cavazza, Giulio Rossi, Claudio Ghimenton, Matteo Brunelli, Maurizio Pea, Marco Chilosi, Lisa Marcolini, Guido Martignoni
Clear cell "sugar" tumor is a rare benign neoplasm arising in the lung, considered as a part of the PEComa family. As PEComas of other sites, this tumor expresses melanocytic markers such as HMB45 and Melan-A. Despite cathepsin K, MITF and CD68 staining are known to be positive in a large number of PEComas and TFE3 rearrangement has been reported in a subset of PEComas, no data is available regarding the expression of these markers and the occurrence of TFE3 and TFEB rearrangement in clear cell "sugar" tumor of the lung...
March 7, 2018: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29508513/nhr-49-hnf4-integrates-regulation-of-fatty-acid-metabolism-with-a-protective-transcriptional-response-to-oxidative-stress-and-fasting
#15
Grace Y S Goh, Johnathan J Winter, Forum Bhanshali, Kelsie R S Doering, Regina Lai, Kayoung Lee, Elizabeth A Veal, Stefan Taubert
Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator-activated receptor α (PPARα), Caenorhabditis elegans NHR-49 is a well-established regulator of lipid metabolism. Here, we reveal that NHR-49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro-longevity gene fmo-2/flavin-containing monooxygenase...
March 5, 2018: Aging Cell
https://www.readbyqxmd.com/read/29507340/map4k3-mediates-amino-acid-dependent-regulation-of-autophagy-via-phosphorylation-of-tfeb
#16
Cynthia L Hsu, Elian X Lee, Kara L Gordon, Edwin A Paz, Wen-Chuan Shen, Kohta Ohnishi, Jill Meisenhelder, Tony Hunter, Albert R La Spada
Autophagy is the major cellular pathway by which macromolecules are degraded, and amino acid depletion powerfully activates autophagy. MAP4K3, or germinal-center kinase-like kinase, is required for robust cell growth in response to amino acids, but the basis for MAP4K3 regulation of cellular metabolic disposition remains unknown. Here we identify MAP4K3 as an amino acid-dependent regulator of autophagy through its phosphorylation of transcription factor EB (TFEB), a transcriptional activator of autophagy, and through amino acid starvation-dependent lysosomal localization of MAP4K3...
March 5, 2018: Nature Communications
https://www.readbyqxmd.com/read/29491374/chloroquine-modulates-antitumor-immune-response-by-resetting-tumor-associated-macrophages-toward-m1-phenotype
#17
Degao Chen, Jing Xie, Roland Fiskesund, Wenqian Dong, Xiaoyu Liang, Jiadi Lv, Xun Jin, Jinyan Liu, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Huafeng Zhang, Ke Tang, Jingwei Ma, Yuying Liu, Bo Huang
Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype...
February 28, 2018: Nature Communications
https://www.readbyqxmd.com/read/29488348/buffering-roles-of-pro-renin-receptor-in-starvation-induced-autophagy-of-skeletal-muscles
#18
Yuki Mizuguchi, Midori Yatabe, Noriko Morishima, Satoshi Morimoto, Atsuhiro Ichihara
Autophagy is an intracellular catabolic process contributing to the regulation of nutrient homeostasis and cellular remodeling. Studies revealed that the nuclear translocation of transcription factor EB (TFEB) plays a key role in lysosomal biogenesis and autophagic pathways. The (pro)renin receptor [(P)RR] is a multifunctional protein playing a pivotal role in regulation of the tissue renin-angiotensin system and is known as an essential constituent of vacuolar H+ -ATPase, considered to be necessary for the autophagy-lysosome pathway...
March 2018: Physiological Reports
https://www.readbyqxmd.com/read/29476714/stat3-contributes-to-lysosomal-mediated-cell-death-in-a-novel-derivative-of-riccardin-d-treated-breast-cancer-cells-in-association-with-tfeb
#19
Lin Li, Bin Sun, Yun Gao, Huanmin Niu, Huiqing Yuan, Hongxiang Lou
RDD648, a novel derivative of a natural molecule riccardin D, exhibited potent anticancer activity by targeting lysosomes in vitro and in vivo. Mechanistic studies revealed that RDD648 facilitated STAT3 translocation into the nucleus, and this activity was involved in lysosome-mediated cell death as evidenced by our finding that inhibition of STAT3 alleviated lysosomal membrane permeabilization. Further investigation indicated that nuclear STAT3 directly interacted with transcription factor TFEB, leading to the partial loss of function of TFEB which is essential for lysosome turnover...
February 21, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29467198/endothelial-tfeb-transcription-factor-eb-positively-regulates-postischemic-angiogenesis
#20
Yanbo Fan, Haocheng Lu, Wenying Liang, Minerva T Garcia-Barrio, Yanhong Guo, Ji Zhang, Tianqing Zhu, Yibai Hao, Jifeng Zhang, Y Eugene Chen
RATIONALE: Postischemic angiogenesis is critical to limit the ischemic tissue damage and improve the blood flow recovery. The regulation and the underlying molecular mechanisms of postischemic angiogenesis are not fully unraveled. TFEB (transcription factor EB) is emerging as a master gene for autophagy and lysosome biogenesis. However, the role of TFEB in vascular disease is less understood. OBJECTIVE: We aimed to determine the role of endothelial TFEB in postischemic angiogenesis and its underlying molecular mechanism...
March 30, 2018: Circulation Research
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