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Yasuhiro Maejima
Autophagy is an evolutionarily conserved process for degradation of long-lived proteins and organelles that govern a number of cardiac pathologies which cause heart failure. Indeed, recent investigations have uncovered pathways that regulate autophagy in the heart and underlying mechanisms by which alterations in this process affect cardiac function and structure. One of the major roles of autophagy in cardiomyocytes is the intracellular protein quality control (PQC). Impairment of autophagy causes aggregation of damaged and/or misfolded proteins in cardiomyocytes, thereby damaging the cells which, in turn leads to pathological cardiac remodeling...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
Yan G Zhao, Hong Zhang
The ER forms contacts with other endomembrane systems to exchange materials (e.g., calcium and lipids) and also to modulate dynamic organelle processes, including fission, cargo sorting and movement. During autophagosome formation, dynamic contacts between the ER and the phagophore membrane are crucial for phagophore expansion and closure. Little is known about the mechanisms underlying the formation and disassembly of the ER contacts. We found that the ER-localized autophagy protein EPG-3/VMP1 plays an essential role in controlling ER-phagophore dissociation and also the disassembly of ER contacts with LDs, mitochondria and endolysosomes...
March 1, 2018: Autophagy
Christina Kary
No abstract text is available yet for this article.
March 2018: Nature Cell Biology
Thomas J Mercer, Andrea Gubas, Sharon A Tooze
Autophagy is a highly conserved process, essential for the maintenance of cellular homeostasis. Autophagy occurs at a basal level in all cells, but can be upregulated during stress, starvation, or infection. Misregulation of autophagy has been linked to various disorders, including cancer, neurodegeneration and immune diseases. Here, we discuss the essential proteins acting in the formation of an autophagosome, with a focus on the ULK and VPS34 kinase complexes, PI3P effector proteins and the transmembrane autophagy-related protein ATG9...
January 25, 2018: Journal of Biological Chemistry
André M Miranda, Zofia M Lasiecka, Yimeng Xu, Jessi Neufeld, Sanjid Shahriar, Sabrina Simoes, Robin B Chan, Tiago Gil Oliveira, Scott A Small, Gilbert Di Paolo
Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes...
January 18, 2018: Nature Communications
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
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
Heeseon An, J Wade Harper
Ribosomes are abundant cellular machines1,2 that are regulated by assembly, supernumerary subunit turnover and nascent chain quality control mechanisms1-5 . 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 reporters8,9 ...
February 2018: Nature Cell Biology
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
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
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
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-P (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 PI3K present in multiple complexes with specific functions and regulation. In yeast, the PI3K complex II consists of Vps34p, Vps15p, Vps30p/Atg6p, and Vps38p, and is essential for vacuolar protein sorting. Here, we describe the Arabidopsis ( Arabidopsis thaliana ) homolog of yeast Vps38p and human UV radiation resistance-associated gene protein...
February 2018: Plant Physiology
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
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
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...
January 2018: Molecular and Biochemical Parasitology
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
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
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...
December 4, 2017: Journal of Cell Biology
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
Jacob New, Levi Arnold, Megha Ananth, Sameer Alvi, Mackenzie Thornton, Lauryn Werner, Ossama Tawfik, Hongying Dai, Yelizaveta Shnayder, Kiran Kakarala, Terance T Tsue, Douglas A Girod, Wen-Xing Ding, Shrikant Anant, Sufi Mary 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...
December 1, 2017: Cancer Research
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