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https://www.readbyqxmd.com/read/28544137/phenotypic-identification-of-a-novel-autophagy-inhibitor-chemotype-targeting-lipid-kinase-vps34
#1
Herbert Waldmann, Lucas Robke, Luca Laraia, Marjorie A Carnero Corrales, Georgios Konstantinidis, Makoto Muroi, André Richters, Michael Winzker, Tobias Engbring, Stefano Tomassi, Nobumoto Watanabe, Hiroyuki Osada, Daniel Rauh, Yaowen Wu, Julian Engel
Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring formation of autophagy-induced puncta indicating accumulation of lipidated cytosolic protein LC3 on the autophagosomal membrane...
May 22, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28542134/phosphorylated-cav1-activates-autophagy-through-an-interaction-with-becn1-under-oxidative-stress
#2
Jihoon Nah, Seung-Min Yoo, Sunmin Jung, Eun Il Jeong, Moonju Park, Bong-Kiun Kaang, Yong-Keun Jung
CAV1/Caveolin1, an integral membrane protein, is involved in caveolae function and cellular signaling pathways. Here, we report that CAV1 is a positive regulator of autophagy under oxidative stress and cerebral ischemic injury. Treatment with hydrogen peroxide enhanced autophagy flux and caused the localization of BECN1 to the mitochondria, whereas these changes were impaired in the absence of CAV1. Among many autophagy signals, only LC3 foci formation in response to hydrogen peroxide was abolished by CAV1 deficiency...
May 25, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28515304/ros-mediated-jnk-activation-contributes-to-hbx-induced-autophagy-via-regulating-beclin-1-bcl-2-interaction
#3
Linmao Zhong, Wanqin Shu, Wangbin Dai, Bo Gao, Sidong Xiong
Autophagy is closely associated with the regulation of Hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for the autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain still elusive. In present investigation, we demonstrated that HBx induced autophagosome formation independent of class I phosphatidylinositol-3 kinase (PI3K)/AKT/mTOR signaling pathway...
May 17, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28498820/lysosomal-regulation-of-cholesterol-homeostasis-in-tuberous-sclerosis-complex-is-mediated-via-npc1-and-ldl-r
#4
Harilaos Filippakis, Nicola Alesi, Barbara Ogorek, Julie Nijmeh, Damir Khabibullin, Catherine Gutierrez, Alexander J Valvezan, James Cunningham, Carmen Priolo, Elizabeth P Henske
Tuberous sclerosis complex (TSC) is a multisystem disease associated with hyperactive mTORC1. The impact of TSC1/2 deficiency on lysosome-mediated processes is not fully understood. We report here that inhibition of lysosomal function using chloroquine (CQ) upregulates cholesterol homeostasis genes in TSC2-deficient cells. This TSC2-dependent transcriptional signature is associated with increased accumulation and intracellular levels of both total cholesterol and cholesterol esters. Unexpectedly, engaging this CQ-induced cholesterol uptake pathway together with inhibition of de novo cholesterol synthesis allows survival of TSC2-deficient, but not TSC2-expressing cells...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28486006/protein-kinase-activity-of-the-glycolytic-enzyme-pgk1-regulates-autophagy-to-promote-tumorigenesis
#5
Xu Qian, Xinjian Li, Zhimin Lu
Macroautophagy/autophagy is a cellular defense response to stress conditions and is crucial for cell homeostasis maintenance. However, the precise mechanism underlying autophagy initiation, especially in response to glutamine deprivation and hypoxia, is yet to be explored. We recently discovered that PGK1 (phosphoglycerate kinase 1), a glycolytic enzyme, functions as a protein kinase, phosphorylating BECN1/Beclin 1 to initiate autophagy. Under glutamine deprivation or hypoxia stimulation, PGK1 is acetylated at K388 by NAA10/ARD1 in an MTOR-inhibition-dependent manner, leading to the interaction between PGK1 and BECN1 and the subsequent phosphorylation of BECN1 at S30 by PGK1...
May 9, 2017: Autophagy
https://www.readbyqxmd.com/read/28483912/an-in-vitro-torc1-kinase-assay-that-recapitulates-the-gtr-independent-glutamine-responsive-torc1-activation-mechanism-on-yeast-vacuoles
#6
Mirai Tanigawa, Tatsuya Maeda
Evolutionarily-conserved TOR complex 1 (TORC1) responds to nutrients, especially amino acids, to promote cell growth. In yeast Saccharomyces cerevisiae, various nitrogen sources activate TORC1 with different efficiencies although the mechanism remains elusive. Leucine, and perhaps other amino acids, was reported to activate TORC1 via the heterodimeric small GTPases Gtr1-Gtr2, the orthologs of the mammalian Rag GTPases. More recently, an alternative Gtr-independent TORC1 activation mechanism that may respond to glutamine was reported, although its molecular detail is not clear...
May 8, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28479384/beclin1-antagonizes-laptm4b-mediated-egfr-overactivation-in-gastric-cancer-cells
#7
Miao Tian, Yu Chen, Dan Tian, Xiaofang Qiao, Zhiming Ma, Jinlong Li
Beclin1 is an essential autophagy regulator and a haploinsufficient tumor-suppressor. Reduced Berclin1 expression has been associated with many types of human malignancies including gastric cancer. However, the mechanism of how Beclin1 represses tumorigenesis of gastric cancer remains elusive. In recent proteomics study, we found that Beclin1 is associated with Lysosome-associated transmembrane protein 4β (LAPTM4B). LAPTM4B plays an important role in promoting the growth and proliferation of tumor cells, it is overexpressed in a variety of solid tumors and serves as a biomarker for tumor therapy...
May 4, 2017: Gene
https://www.readbyqxmd.com/read/28468885/rubicon-modulates-antiviral-type-i-ifn-signaling-by-targeting-irf3-dimerization
#8
Jae-Hoon Kim, Tae-Hwan Kim, Hyun-Cheol Lee, Chamilani Nikapitiya, Md Bashir Uddin, Min-Eun Park, Eun Seo Lee, Kiramage Chathuranga, Thilina U B Herath, W A Gayan Chathuranga, Jong-Soo Lee
Rubicon is a part of a Beclin-1-Vps34-containing autophagy complex. Rubicon induces antimicrobial responses upon TLR stimulation, and functions as a feedback inhibitor to prevent unbalanced proinflammatory responses depending on dectin-1 signaling. However, the role played by Rubicon during antiviral immune responses, particularly the type I interferon responses remains largely unknown. Here, we report that Rubicon acts as a negative regulator for virus-triggered IFN signaling. Knockdown of Rubicon promoted type I interferon signaling and inhibited virus replication, while overexpression of Rubicon has the opposite effect...
May 3, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28455411/the-vps-34-pi3-kinase-negatively-regulates-rab-5-during-endosome-maturation
#9
Fiona Law, Jung Hwa Seo, Ziqing Wang, Jennifer L DeLeon, Yousstina Bolis, Ashley Brown, Wei-Xing Zong, Guangwei Du, Christian E Rocheleau
The Rab5 GTPase and phosphatidylinositol-3 phosphate (PI(3)P) coordinately regulate endosome trafficking. Rab5 recruits Vps34, the class III PI3-kinase (PI3K), to generate PI(3)P and recruit PI(3)P binding proteins. Loss of Rab5 and loss of Vps34 have opposite effects on endosome size suggesting that our understanding of how Rab5 and PI(3)P cooperate is incomplete. Here we report a novel regulatory loop, whereby C. elegans VPS-34 inactivates RAB-5 via recruitment of the TBC-2 Rab GTPase Activating Protein. We found that loss of VPS-34 caused a large late endosome phenotype like that of loss of TBC-2, and that Rab5 activity is increased in Vps34 knockout mouse embryonic fibroblasts...
April 28, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28436000/foxo3a-suppression-and-vps34-activity-are-essential-to-anti-atrophic-effects-of-leucine-in-skeletal-muscle
#10
Igor L Baptista, João G Silvestre, William J Silva, Siegfried Labeit, Anselmo S Moriscot
Our aim is to gain insight into the mechanisms underlying the anti-atrophic effects of leucine, namely, the way that this amino acid can restrain the up-regulation of MuRF1 and Mafbx/Atrogin-1 in muscle atrophy. Male rats received dietary leucine supplementation for 1-3 days, during which time their hind limbs were immobilized. Our results showed that leucine inhibited Forkhead Box O3 (FoxO3a) translocation to cell nuclei. In addition, leucine was able to reverse the expected reduction of FoXO3a ubiquitination caused by immobilization...
April 24, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28376509/activation-of-g%C3%AE-q-in-cardiomyocytes-increases-vps34-activity-and-stimulates-autophagy
#11
Shengnan Liu, Ya-Ping Jiang, Lisa M Ballou, Wei-Xing Zong, Richard Z Lin
Receptors that activate the heterotrimeric G protein Gαq are thought to play a role in the development of heart failure. Dysregulation of autophagy occurs in some pathological cardiac conditions including heart failure, but whether Gαq is involved in this process is unknown. We used a cardiomyocyte-specific transgenic mouse model of inducible Gαq activation (termed GαqQ209L) to address this question. After 7 days of Gαq activation, GαqQ209L hearts contained more autophagic vacuoles than wild type hearts...
April 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28376477/osteopontin-promotes-cell-migration-and-invasion-and-inhibits-apoptosis-and-autophagy-in-colorectal-cancer-by-activating-the-p38-mapk-signaling-pathway
#12
Ren-Hong Huang, Ying-Jun Quan, Jin-Hong Chen, Ting-Feng Wang, Ming Xu, Min Ye, Hao Yuan, Chong-Jie Zhang, Xiao-Jian Liu, Zhi-Jun Min
BACKGROUND: Osteopontin (OPN) is highly expressed in colorectal cancer (CRC) and is associated with disease progression in vivo. High levels of OPN have been demonstrated to predict low survival rates in CRC. Autophagy is a process of self-digestion, which is thought to play a significant role in carcinogenesis. However, the mechanisms of OPN's effects on CRC cell autophagy have not been elucidated. Therefore, we aimed to investigate possible mechanisms of OPN's effects on CRC autophagy...
April 3, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28351972/erbb2-regulates-autophagic-flux-to-modulate-the-proteostasis-of-app-ctfs-in-alzheimer-s-disease
#13
Bo-Jeng Wang, Guor Mour Her, Ming-Kuan Hu, Yun-Wen Chen, Ying-Tsen Tung, Pei-Yi Wu, Wen-Ming Hsu, Hsinyu Lee, Lee-Way Jin, Sheng-Ping L Hwang, Rita P-Y Chen, Chang-Jen Huang, Yung-Feng Liao
Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34-Vps15 complex independent of its kinase activity...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28306502/pacer-mediates-the-function-of-class-iii-pi3k-and-hops-complexes-in-autophagosome-maturation-by-engaging-stx17
#14
Xiawei Cheng, Xiuling Ma, Xianming Ding, Lin Li, Xiao Jiang, Zhirong Shen, She Chen, Wei Liu, Weihua Gong, Qiming Sun
Class III PI3-kinase (PI3KC3) is essential for autophagy initiation, but whether PI3KC3 participates in other steps of autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. Here, we report Pacer (protein associated with UVRAG as autophagy enhancer) as a regulator of autophagy. Pacer localizes to autophagic structures and positively regulates autophagosome maturation. Mechanistically, Pacer antagonizes Rubicon to stimulate Vps34 kinase activity...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28302665/calpain-mobilizes-atg9-bif-1-vesicles-from-golgi-stacks-upon-autophagy-induction-by-thapsigargin
#15
Elena Marcassa, Marzia Raimondi, Tahira Anwar, Eeva-Liisa Eskelinen, Michael P Myers, Gianluca Triolo, Claudio Schneider, Francesca Demarchi
CAPNS1 is essential for stability and function of the ubiquitous calcium-dependent proteases micro- and milli-calpain. Upon inhibition of the endoplasmic reticulum Ca(2+) ATPase by 100 nM thapsigargin, both micro-calpain and autophagy are activated in human U2OS osteosarcoma cells in a CAPNS1-dependent manner. As reported for other autophagy triggers, thapsigargin treatment induces Golgi fragmentation and fusion of Atg9/Bif-1-containing vesicles with LC3 bodies in control cells. By contrast, CAPNS1 depletion is coupled with an accumulation of LC3 bodies and Rab5 early endosomes...
May 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28299793/foxo1-ampk-ulk1-regulates-ethanol-induced-autophagy-in-muscle-by-enhanced-atg14-association-with-the-becn1-pik3c3-complex
#16
Ly Q Hong-Brown, C Randell Brown, Maithili Navaratnarajah, Charles H Lang
BACKGROUND: Excessive alcohol (EtOH) consumption causes an imbalance in protein metabolism. EtOH impairs protein synthesis in C2C12 myoblasts via a FoxO1-AMPK-TSC2-mTORC1 pathway and also induces protein degradation. As the underlying regulatory signaling cascades for these processes are currently poorly defined, we tested the hypothesis that alcohol-induced autophagy is mediated via activation of the PIK3C3 complex that is regulated by FoxO1-AMPK. METHODS: C2C12 myoblasts were incubated with EtOH for various periods of time, and autophagy pathway-related proteins were assessed by Western blotting and immunoprecipitation...
May 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/28253972/in-vitro-characterization-of-vps34-lipid-kinase-inhibition-by-small-molecules
#17
F Fassy, C Dureuil, A Lamberton, M Mathieu, N Michot, B Ronan, B Pasquier
VPS34 is a class III phosphoinositide 3-kinase that acts on vesicle trafficking. This kinase has recently attracted significant attention because of the function it plays in the machinery involved in the early steps of autophagy. Moreover, because significant progress had been made in the optimization of specific kinase inhibitors, its potential to be targeted by catalytic inhibitors has been investigated by different groups. The aim of this review is to present the key in vitro assays necessary for characterizing inhibitors of the catalytic activity of VPS34...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28253968/study-of-ulk1-catalytic-activity-and-its-regulation
#18
B Stork, J Dengjel
During the last decade, the molecular mechanisms controlling the initiation of (macro-)autophagy have been extensively studied. Two macromolecular kinase complexes are central for the initiation of autophagy: the protein kinase unc-51-like kinase 1 (ULK1) complex and the lipid kinase VPS34/Beclin 1 complex. The serine/threonine kinase ULK1 represents the mammalian ortholog of yeast autophagy-related (Atg) protein 1 (Atg1). ULK1 is regulated by upstream nutrient- and energy-sensing kinases, and transmits these signals to the core autophagic machinery...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28253963/fluorescence-based-assays-to-analyse-phosphatidylinositol-5-phosphate-in-autophagy
#19
M Vicinanza, M J Gratian, M Bowen, D C Rubinsztein
Autophagosome formation is stimulated by VPS34-dependent PI(3)P formation and by alternative VPS34-independent pathways. We recently described that PI(5)P regulates autophagosome biogenesis and rescues autophagy in VPS34-inactivated cells, suggesting that PI(5)P contributes to canonical autophagy. Our analysis revealed a hitherto unknown functional interplay between PIKfyve and PIPK type II in controlling PI(5)P levels in the context of autophagy. Among phosphoinositides, visualization of PI(5)P in intact cells has remained difficult...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28253960/fluorescent-fyve-chimeras-to-quantify-ptdins3p-synthesis-during-autophagy
#20
S M S Yakhine-Diop, G Martínez-Chacón, R A González-Polo, J M Fuentes, M Niso-Santano
Autophagy is the major cellular process of degradation and is modulated by several signaling pathways. Phosphatidylinositol 3-kinase (PtdIns3K) class III (Vps34) and PtdIns3K class I regulate the autophagy pathway positively and negatively, respectively. Both classes of PtdIns3K participate in the synthesis of phosphatidylinositol 3-phosphate (PtdIns3P), which plays a crucial role in autophagosome biogenesis and membrane traffic. PtdIns3P is a membrane phospholipid that is associated with endogenous FYVE domain-containing proteins...
2017: Methods in Enzymology
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