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https://www.readbyqxmd.com/read/29313410/ulk1-phosphorylates-ser30-of-becn1-in-association-with-atg14-to-stimulate-autophagy-induction
#1
Ji-Man Park, Minchul Seo, Chang Hwa Jung, Douglas Grunwald, Matthew Stone, Neil Michael Otto, Erik Toso, Yeseul Ahn, Michael Kyba, Timothy J Griffin, LeeAnn Higgins, Do-Hyung Kim
ULK1 (unc51-like autophagy activating kinase 1) is a serine/threonine kinase that plays a key role in regulating macroautophagy/autophagy induction in response to amino acid starvation. Despite the recent progress in understanding ULK1 functions, the molecular mechanism by which ULK1 regulates the induction of autophagy remains elusive. In this study, we determined that ULK1 phosphorylates Ser30 of BECN1 (beclin 1) in association with ATG14 (autophagy related 14) but not with UVRAG (UV radiation resistance associated)...
January 9, 2018: Autophagy
https://www.readbyqxmd.com/read/29311744/mutations-in-vps15-perturb-neuronal-migration-in-mice-and-are-associated-with-neurodevelopmental-disease-in-humans
#2
Thomas Gstrein, Andrew Edwards, Anna Přistoupilová, Ines Leca, Martin Breuss, Sandra Pilat-Carotta, Andi H Hansen, Ratna Tripathy, Anna K Traunbauer, Tobias Hochstoeger, Gavril Rosoklija, Marco Repic, Lukas Landler, Viktor Stránecký, Gerhard Dürnberger, Thomas M Keane, Johannes Zuber, David J Adams, Jonathan Flint, Tomas Honzik, Marta Gut, Sergi Beltran, Karl Mechtler, Elliott Sherr, Stanislav Kmoch, Ivo Gut, David A Keays
The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration. We show that this is caused by a hypomorphic mutation in Vps15 that perturbs endosomal-lysosomal trafficking and autophagy, resulting in an upregulation of Nischarin, which inhibits Pak1 signaling...
January 8, 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29230017/systematic-analysis-of-ribophagy-in-human-cells-reveals-bystander-flux-during-selective-autophagy
#3
Heeseon An, J Wade Harper
Ribosomes are abundant cellular machines 1,2 that are regulated by assembly, supernumerary subunit turnover and nascent chain quality control mechanisms 1-5 . Moreover, nitrogen starvation in yeast has been reported to promote selective ribosome delivery to the vacuole in an autophagy conjugation system dependent manner, a process called 'ribophagy' 6,7 . However, whether ribophagy in mammals is selective or regulated is unclear. Using Ribo-Keima flux reporters, we find that starvation or mTOR inhibition promotes VPS34-dependent ribophagic flux, which, unlike yeast, is largely independent of ATG8 conjugation and occurs concomitantly with other cytosolic protein autophagic flux reporters 8,9 ...
December 11, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/29228587/chronic-myeloid-leukemia-progenitor-cells-require-autophagy-when-leaving-hypoxia-induced-quiescence
#4
Angela Ianniciello, Pierre-Yves Dumas, Claire Drullion, Amélie Guitart, Arnaud Villacreces, Yan Peytour, Jean Chevaleyre, Philippe Brunet de la Grange, Isabelle Vigon, Vanessa Desplat, Muriel Priault, Persio Dello Sbarba, Zoran Ivanovic, François-Xavier Mahon, Jean-Max Pasquet
Albeit tyrosine kinase inhibitors anti-Abl used in Chronic Myeloid Leukemia (CML) block the deregulated activity of the Bcr-Abl tyrosine kinase and induce remission in 90% of patients, they do not eradicate immature hematopoietic compartments of leukemic stem cells. To elucidate if autophagy is important for stem cell survival and/or proliferation, we used culture in low oxygen concentration (0.1% O2 for 7 days) followed back by non-restricted O2 supply (normoxic culture) to mimic stem cell proliferation and commitment...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29209653/unveiling-the-role-of-vps34-kinase-domain-dynamics-in-regulation-of-the-autophagic-pi3k-complex
#5
Goran Stjepanovic, Sulochanadevi Baskaran, Mary G Lin, James H Hurley
The class III PI 3-kinase, VPS34 forms distinct complexes essential for cargo sorting and membrane trafficking in endocytosis as well as for autophagosome nucleation and maturation. We used integrative structural biology approach to provide insights into the conformational dynamics of the complex and mechanisms that regulate VPS34 activity at the membrane.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29186924/regulation-of-the-tumor-suppressor-beclin-1-by-distinct-ubiquitination-cascades
#6
REVIEW
Fahd Boutouja, Rebecca Brinkmeier, Thomas Mastalski, Fouzi El Magraoui, Harald W Platta
Autophagy contributes to cellular homeostasis through the degradation of various intracellular targets such as proteins, organelles and microbes. This relates autophagy to various diseases such as infections, neurodegenerative diseases and cancer. A central component of the autophagy machinery is the class III phosphatidylinositol 3-kinase (PI3K-III) complex, which generates the signaling lipid phosphatidylinositol 3-phosphate (PtdIns3P). The catalytic subunit of this complex is the lipid-kinase VPS34, which associates with the membrane-targeting factor VPS15 as well as the multivalent adaptor protein BECLIN 1...
November 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29184027/arabidopsis-vps38-is-required-for-vacuolar-trafficking-but-dispensable-for-autophagy
#7
Han Nim Lee, Xavier Zarza, Jeong Hun Kim, Min Ji Yoon, Sang-Hoon Kim, Jae-Hoon Lee, Nadine Paris, Teun Munnik, Marisa S Otegui, Taijoon Chung
Phosphatidylinositol 3-phosphate (PI3P) is a signaling molecule that controls a variety of processes in endosomal, autophagic and vacuolar/lysosomal trafficking in yeasts and mammals. Vacuolar protein sorting 34 (Vps34) is a conserved phosphatidylinositol 3-kinase (PI3K) present in multiple complexes with specific functions and regulation. In yeast, the PI3K complex II, consisting of Vps34p, Vps15p, Vps30p/Atg6p, and Vps38p, is essential for vacuolar protein sorting. Here, we describe the Arabidopsis thaliana homolog of yeast Vps38p and human UV radiation resistance-associated gene (UVRAG) protein...
November 28, 2017: Plant Physiology
https://www.readbyqxmd.com/read/29180704/vps34-pi-3-kinase-inactivation-enhances-insulin-sensitivity-through-reprogramming-of-mitochondrial-metabolism
#8
Benoit Bilanges, Samira Alliouachene, Wayne Pearce, Daniele Morelli, Gyorgy Szabadkai, Yuen-Li Chung, Gaëtan Chicanne, Colin Valet, Julia M Hill, Peter J Voshol, Lucy Collinson, Christopher Peddie, Khaled Ali, Essam Ghazaly, Vinothini Rajeeve, Georgios Trichas, Shankar Srinivas, Claire Chaussade, Rachel S Salamon, Jonathan M Backer, Cheryl L Scudamore, Maria A Whitehead, Erin P Keaney, Leon O Murphy, Robert K Semple, Bernard Payrastre, Sharon A Tooze, Bart Vanhaesebroeck
Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. The organismal impact of systemic inhibition of Vps34 kinase activity is not completely understood. Here we show that heterozygous Vps34 kinase-dead mice are healthy and display a robustly enhanced insulin sensitivity and glucose tolerance, phenotypes mimicked by a selective Vps34 inhibitor in wild-type mice. The underlying mechanism of insulin sensitization is multifactorial and not through the canonical insulin/Akt pathway...
November 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29163768/inhibitor-of-growth-protein-4-interacts-with-beclin-1-and-represses-autophagy
#9
Valentina Sica, José Manuel Bravo-San Pedro, Guo Chen, Guillermo Mariño, Sylvie Lachkar, Valentina Izzo, Maria Chiara Maiuri, Mireia Niso-Santano, Guido Kroemer
Beclin 1 (BECN1) is a multifunctional protein that activates the pro-autophagic class III phosphatidylinositol 3-kinase (PIK3C3, best known as VPS34), yet also interacts with multiple negative regulators. Here we report that BECN1 interacts with inhibitor of growth family member 4 (ING4), a tumor suppressor protein that is best known for its capacity to interact with the tumor suppressor protein p53 (TP53) and the acetyltransferase E1A binding protein p300 (EP300). Removal of TP53 or EP300 did not affect the BECN1/ING4 interaction, which however was lost upon culture of cells in autophagy-inducing, nutrient free conditions...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29155083/tbvps15-is-required-for-vesicular-transport-and-cytokinesis-in-trypanosoma-brucei
#10
Alejandra C Schoijet, Kildare Miranda, Tamara Sternlieb, Nadia M Barrera, Wendell Girard-Dias, Wanderley de Souza, Guillermo D Alonso
The class III phosphatidylinositol 3-kinase (PI3K) Vps34 is an important regulator of key cellular functions, including cell growth, survival, intracellular trafficking, autophagy and nutrient sensing. In yeast, Vps34 is associated with the putative serine/threonine protein kinase Vps15, however, its role in signaling has not been deeply evaluated. Here, we have identified the Vps15 orthologue in Trypanosoma brucei, named TbVps15. Knockdown of TbVps15 expression by interference RNA resulted in inhibition of cell growth and blockage of cytokinesis...
November 16, 2017: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/29089378/ph-of-endophagosomes-controls-association-of-their-membranes-with-vps34-and-ptdins-3-p-levels
#11
Amriya Naufer, Victoria E B Hipolito, Suriakarthiga Ganesan, Akriti Prashar, Vanina Zaremberg, Roberto J Botelho, Mauricio R Terebiznik
Phagocytosis of filamentous bacteria occurs through tubular phagocytic cups (tPCs) and takes many minutes to engulf these filaments into phagosomes. Contravening the canonical phagocytic pathway, tPCs mature by fusing with endosomes. Using this model, we observed the sequential recruitment of early and late endolysosomal markers to the elongating tPCs. Surprisingly, the regulatory early endosomal lipid phosphatidylinositol-3-phosphate (PtdIns(3)P) persists on tPCs as long as their luminal pH remains neutral...
October 31, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29066608/molecular-mechanisms-of-developmentally-programmed-crinophagy-in-drosophila
#12
Tamás Csizmadia, Péter Lőrincz, Krisztina Hegedűs, Szilvia Széplaki, Péter Lőw, Gábor Juhász
At the onset of metamorphosis, Drosophila salivary gland cells undergo a burst of glue granule secretion to attach the forming pupa to a solid surface. Here, we show that excess granules evading exocytosis are degraded via direct fusion with lysosomes, a secretory granule-specific autophagic process known as crinophagy. We find that the tethering complex HOPS (homotypic fusion and protein sorting); the small GTPases Rab2, Rab7, and its effector, PLEKHM1; and a SNAP receptor complex consisting of Syntaxin 13, Snap29, and Vamp7 are all required for the fusion of secretory granules with lysosomes...
October 24, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29030394/ptdins3p-controls-mtorc1-signaling-through-lysosomal-positioning
#13
Zhi Hong, Nina Marie Pedersen, Ling Wang, Maria Lyngaas Torgersen, Harald Stenmark, Camilla Raiborg
The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase complex that localizes to lysosomes to up-regulate anabolic processes and down-regulate autophagy. Although mTORC1 is known to be activated by lysosome positioning and by amino acid-stimulated production of phosphatidylinositol 3-phosphate (PtdIns3P) by the lipid kinase VPS34/PIK3C3, the mechanisms have been elusive. Here we present results that connect these seemingly unrelated pathways for mTORC1 activation. Amino acids stimulate recruitment of the PtdIns3P-binding protein FYCO1 to lysosomes and promote contacts between FYCO1 lysosomes and endoplasmic reticulum that contain the PtdIns3P effector Protrudin...
October 13, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28980854/pik3c3-vps34-control-by-acetylation
#14
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/28972076/secretory-autophagy-in-cancer-associated-fibroblasts-promotes-head-and-neck-cancer-progression-and-offers-a-novel-therapeutic-target
#15
Jacob New, Levi Arnold, Megha Ananth, Sameer Alvi, Mackenzie Thornton, Lauryn R Werner, Ossama Tawfik, Hongying Dai, Yelizaveta Shnayder, Kiran Kakarala, Terance Ted Tsue, Douglas A Girod, Wen-Xing Ding, Shrikant Anant, Sufi M Thomas
Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion...
September 28, 2017: Cancer Research
https://www.readbyqxmd.com/read/28904211/zonda-is-a-novel-early-component-of-the-autophagy-pathway-in-drosophila
#16
Mariana Melani, Ayelén Valko, Nuria M Romero, Milton O Aguilera, Julieta M Acevedo, Zambarlal Bhujabal, Joel Perez-Perri, Rocío V de la Riva-Carrasco, Maximiliano J Katz, Eleonora Sorianello, Cecilia D'Alessio, Gabor Juhász, Terje Johansen, María I Colombo, Pablo Wappner
Autophagy is an evolutionary conserved process by which eukaryotic cells undergo self-digestion of cytoplasmic components. Here we report that a novel Drosophila immunophilin, which we have named Zonda, is critically required for starvation-induced autophagy. We show that Zonda operates at early stages of the process, specifically for Vps34-mediated phosphatidylinositol 3-phosphate (PI3P) deposition. Zonda displays an even distribution under basal conditions and, soon after starvation, nucleates in endoplasmic reticulum-associated foci that colocalize with omegasome markers...
November 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28903944/a-dual-role-for-the-class-iii-pi3k-vps34-in-platelet-production-and-thrombus-growth
#17
Colin Valet, Marie Levade, Gaëtan Chicanne, Benoit Bilanges, Cendrine Cabou, Julien Viaud, Marie-Pierre Gratacap, Frédérique Gaits-Iacovoni, Bart Vanhaesebroeck, Bernard Payrastre, Sonia Severin
To uncover the role of Vps34, the sole class III phosphoinositide 3-kinase (PI3K), in megakaryocytes (MKs) and platelets, we created a mouse model with Vps34 deletion in the MK/platelet lineage (Pf4-Cre/Vps34(lox/lox)). Deletion of Vps34 in MKs led to the loss of its regulator protein, Vps15, and was associated with microthrombocytopenia and platelet granule abnormalities. Although Vps34 deficiency did not affect MK polyploidisation or proplatelet formation, it dampened MK granule biogenesis and directional migration toward an SDF1α gradient, leading to ectopic platelet release within the bone marrow...
November 2, 2017: Blood
https://www.readbyqxmd.com/read/28882875/class-iii-pi3k-positively-regulates-platelet-activation-and-thrombosis-via-pi-3-p-directed-function-of-nadph-oxidase
#18
Yangyang Liu, Mengjiao Hu, Dongjiao Luo, Ming Yue, Shuai Wang, Xiaoyan Chen, Yangfan Zhou, Yi Wang, Yanchun Cai, Xiaolan Hu, Yuehai Ke, Zhongzhou Yang, Hu Hu
OBJECTIVE: Class III phosphoinositide 3-kinase, also known as VPS34 (vacuolar protein sorting 34), is a highly conserved enzyme regulating important cellular functions such as NADPH oxidase (NOX) assembly, membrane trafficking, and autophagy. Although VPS34 is expressed in platelets, its involvement in platelet activation remains unclear. Herein, we investigated the role of VPS34 in platelet activation and thrombus formation using VPS34 knockout mice. APPROACH AND RESULTS: Platelet-specific VPS34-deficient mice were generated and characterized...
November 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28877469/autophagy-independent-lysosomal-targeting-regulated-by-ulk1-2-fip200-and-atg9
#19
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/28872463/mtorc1-hyperactivation-arrests-bone-growth-in-lysosomal-storage-disorders-by-suppressing-autophagy
#20
Rosa Bartolomeo, Laura Cinque, Chiara De Leonibus, Alison Forrester, Anna Chiara Salzano, Jlenia Monfregola, Emanuela De Gennaro, Edoardo Nusco, Isabella Azario, Carmela Lanzara, Marta Serafini, Beth Levine, Andrea Ballabio, Carmine Settembre
The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs)...
October 2, 2017: Journal of Clinical Investigation
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