75 research outputs found

    Sequential SNARE disassembly and GATE-16–GOS-28 complex assembly mediated by distinct NSF activities drives Golgi membrane fusion

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    Characterization of mammalian NSF (G274E) and Drosophila NSF (comatose) mutants revealed an evolutionarily conserved NSF activity distinct from ATPase-dependent SNARE disassembly that was essential for Golgi membrane fusion. Analysis of mammalian NSF function during cell-free assembly of Golgi cisternae from mitotic Golgi fragments revealed that NSF disassembles Golgi SNAREs during mitotic Golgi fragmentation. A subsequent ATPase-independent NSF activity restricted to the reassembly phase is essential for membrane fusion. NSF/α-SNAP catalyze the binding of GATE-16 to GOS-28, a Golgi v-SNARE, in a manner that requires ATP but not ATP hydrolysis. GATE-16 is essential for NSF-driven Golgi reassembly and precludes GOS-28 from binding to its cognate t-SNARE, syntaxin-5. We suggest that this occurs at the inception of Golgi reassembly to protect the v-SNARE and regulate SNARE function

    Spatial proteomics reveals secretory pathway disturbances caused by neuropathy-associated TECPR2

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    Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare fatal neurological disease caused by mis- and nonsense mutations in the gene encoding for Tectonin beta-propeller repeat containing protein 2 (TECPR2). While TECPR2 is required for lysosomal consumption of autophagosomes and ER-to-Golgi transport, it remains elusive how exactly TECPR2 is involved in autophagy and secretion and what downstream sequels arise from defective TECPR2 due to its involvement in these processes. To address these questions, we determine molecular consequences of TECPR2 deficiency along the secretory pathway. By employing spatial proteomics, we describe pronounced changes with numerous proteins important for neuronal function being affected in their intracellular transport. Moreover, we provide evidence that TECPR2's interaction with the early secretory pathway is not restricted to COPII carriers. Collectively, our systematic profiling of a HSAN9 cell model points to specific trafficking and sorting defects which might precede autophagy dysfunction upon TECPR2 deficiency. Disease-associated mutations in the protein TECPR2 have so far been mainly studied with respect to autophagy. Using complementary proteomics approaches, the authors identify trafficking and sorting defects along the secretory pathway upon TECPR2 deficiency and provide evidence that TECPR2 associates with the ER-Golgi interface

    Driving next-generation autophagy researchers towards translation (DRIVE), an international PhD training program on autophagy

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    The European autophagy consortium Driving next-generation autophagy researchers towards translation (DRIVE) held its kick-off meeting in Groningen on the 14(th) and 15(th) of June 2018. This Marie Sklodowska-Curie Early Training Network was approved under the European Union's Horizon 2020 Research and Innovation Program and is funded for 4 years. Within DRIVE, 14 European research teams from academia and industry will train 15 PhD students through applied, cross-disciplinary and collaborative macroautophagy/autophagy research. The goal of DRIVE is to stimulate applied approaches in autophagy research and provide training towards translation, while advancing our knowledge on autophagy in specific physiological and pathological states. The strong focus on translation will prepare the PhD students to be at the forefront to exploit autophagy for the development of therapies directly benefitting patients. Thereby, DRIVE will contribute to filling the educational gap that currently exists between academia and industry, and will prepare its PhD students for alternative and highly flexible professional paths.Non peer reviewe

    Driving next-generation autophagy researchers towards translation (DRIVE), an international PhD training program on autophagy

    Get PDF
    The European autophagy consortium Driving next-generation autophagy researchers towards translation (DRIVE) held its kick-off meeting in Groningen on the 14th and 15th of June 2018. This Marie SkƂodowska-Curie Early Training Network was approved under the European Union's Horizon 2020 Research and Innovation Program and is funded for 4 years. Within DRIVE, 14 European research teams from academia and industry will train 15 PhD students through applied, cross-disciplinary and collaborative macroautophagy/autophagy research. The goal of DRIVE is to stimulate applied approaches in autophagy research and provide training towards translation, while advancing our knowledge on autophagy in specific physiological and pathological states. The strong focus on translation will prepare the PhD students to be at the forefront to exploit autophagy for the development of therapies directly benefitting patients. Thereby, DRIVE will contribute to filling the educational gap that currently exists between academia and industry, and will prepare its PhD students for alternative and highly flexible professional path

    Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence:Supporting the next generation of autophagy researchers and fostering international collaborations

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    Recently, NIH has funded a center for autophagy research named the Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center (UNM HSC), with aspirations to promote autophagy research locally, nationally, and internationally. The center has 3 major missions: (i) to support junior faculty in their endeavors to develop investigations in this area and obtain independent funding; (ii) to develop and provide technological platforms to advance autophagy research with emphasis on cellular approaches for high quality reproducible research; and (iii) to foster international collaborations through the formation of an International Council of Affiliate Members and through hosting national and international workshops and symposia. Scientifically, the AIM center is focused on autophagy and its intersections with other processes, with emphasis on both fundamental discoveries and applied translational research.</p

    Beth Levine in memoriam

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    Beth Levine was born on 7 April 1960 in Newark, New Jersey. She went to college at Brown University where she received an A.B. Magna Cum Laude, and she attended medical school at Cornell University Medical College, receiving her MD in 1986. She completed her internship and residency in Internal Medicine at Mount Sinai Hospital in New York, and her fellowship in Infectious Diseases at The Johns Hopkins Hospital. Most recently, Beth was a Professor of Internal Medicine and Microbiology, Director of the Center for Autophagy Research, and holder of the Charles Sprague Distinguished Chair in Biomedical Science at the University of Texas Southwestern Medical Center in Dallas. Beth died on 15 June 2020 from cancer. Beth is survived by her husband, Milton Packer, and their two children, Rachel (26 years old) and Ben (25 years old). Dr. Levine was as an international leader in the field of autophagy research. Her laboratory identified the mammalian autophagy gene BECN1/beclin 1; identified conserved mechanisms underlying the regulation of autophagy (e.g. BCL2-BECN1 complex formation, insulin-like signaling, EGFR, ERBB2/HER2 and AKT1-mediated BECN1 phosphosphorylation); and provided the first evidence that autophagy genes are important in antiviral host defense, tumor suppression, lifespan extension, apoptotic corpse clearance, metazoan development, Na,K-ATPase-regulated cell death, and the beneficial metabolic effects of exercise. She developed a potent autophagy-inducing cell permeable peptide, Tat-beclin 1, which has potential therapeutic applications in a range of diseases. She was a founding Associate Editor of the journal Autophagy and an editorial board member of Cell and Cell Host & Microbe. She has received numerous awards/honors in recognition of her scientific achievement, including: The American Cancer Society Junior Faculty Research Award (1994); election into the American Society of Clinical Investigation (2000); the Ellison Medical Foundation Senior Scholars Award in Global Infectious Diseases (2004); elected member, American Association of Physicians (2005); appointment as a Howard Hughes Medical Institute Investigator (2008); Edith and Peter O’Donnell Award in Medicine (2008); elected fellow, American Association for the Advancement of Science (2012); election into the National Academy of Sciences (2013); election into the Academy of Medicine, Engineering and Science of Texas (2013); the ASCI Stanley J. Korsmeyer Award (2014); Phyllis T. Bodel Women in Medicine Award, Yale University School of Medicine (2018); recipient, Barcroft Medal, Queen’s University Belfast (2018).Fil: An, Zhenyi. No especifĂ­ca;Fil: Ballabi, Andrea. No especifĂ­ca;Fil: Bennett, Lynda. No especifĂ­ca;Fil: Boya, Patricia. No especifĂ­ca;Fil: Cecconi, Francesco. No especifĂ­ca;Fil: Chiang, Wei Chung. No especifĂ­ca;Fil: Codogno, Patrice. No especifĂ­ca;Fil: Colombo, Maria Isabel. No especifĂ­ca;Fil: Cuervo, Ana Maria. No especifĂ­ca;Fil: Debnath, Jayanta. No especifĂ­ca;Fil: Deretic, Vojo. No especifĂ­ca;Fil: Dikic, Ivan. No especifĂ­ca;Fil: Dionne, Keith. No especifĂ­ca;Fil: Dong, Xiaonan. No especifĂ­ca;Fil: Elazar, Zvulun. No especifĂ­ca;Fil: Galluzzi, Lorenzo. No especifĂ­ca;Fil: Gentile, Frank. No especifĂ­ca;Fil: Griffin, Diane E.. No especifĂ­ca;Fil: Hansen, Malene. No especifĂ­ca;Fil: Hardwick, J. Marie. No especifĂ­ca;Fil: He, Congcong. No especifĂ­ca;Fil: Huang, Shu Yi. No especifĂ­ca;Fil: Hurley, James. No especifĂ­ca;Fil: Jackson, William T.. No especifĂ­ca;Fil: Jozefiak, Cindy. No especifĂ­ca;Fil: Kitsis, Richard N.. No especifĂ­ca;Fil: Klionsky, Daniel J.. No especifĂ­ca;Fil: Kroemer, Guido. No especifĂ­ca;Fil: Meijer, Alfred J.. No especifĂ­ca;Fil: MelĂ©ndez, Alicia. No especifĂ­ca;Fil: Melino, Gerry. No especifĂ­ca;Fil: Mizushima, Noboru. No especifĂ­ca;Fil: Murphy, Leon O.. No especifĂ­ca;Fil: Nixon, Ralph. No especifĂ­ca;Fil: Orvedahl, Anthony. No especifĂ­ca;Fil: Pattingre, Sophie. No especifĂ­ca;Fil: Piacentini, Mauro. No especifĂ­ca;Fil: Reggiori, Fulvio. No especifĂ­ca;Fil: Ross, Theodora. No especifĂ­ca;Fil: Rubinsztein, David C.. No especifĂ­ca;Fil: Ryan, Kevin. No especifĂ­ca;Fil: Sadoshima, Junichi. No especifĂ­ca;Fil: Schreiber, Stuart L.. No especifĂ­ca;Fil: Scott, Frederick. No especifĂ­ca;Fil: Sebti, Salwa. No especifĂ­ca;Fil: Shiloh, Michael. No especifĂ­ca;Fil: Shoji, Sanae. No especifĂ­ca;Fil: Simonsen, Anne. No especifĂ­ca;Fil: Smith, Haley. No especifĂ­ca;Fil: Sumpter, Kathryn M.. No especifĂ­ca;Fil: Thompson, Craig B.. No especifĂ­ca;Fil: Thorburn, Andrew. No especifĂ­ca;Fil: Thumm, Michael. No especifĂ­ca;Fil: Tooze, Sharon. No especifĂ­ca;Fil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de BioquĂ­mica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de BioquĂ­mica y Medicina Molecular; ArgentinaFil: Virgin, Herbert W.. No especifĂ­ca;Fil: Wang, Fei. No especifĂ­ca;Fil: White, Eileen. No especifĂ­ca;Fil: Xavier, Ramnik J.. No especifĂ­ca;Fil: Yoshimori, Tamotsu. No especifĂ­ca;Fil: Yuan, Junying. No especifĂ­ca;Fil: Yue, Zhenyu. No especifĂ­ca;Fil: Zhong, Qing. No especifĂ­ca

    Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence: supporting the next generation of autophagy researchers and fostering international collaborations

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    Recently, NIH has funded a center for autophagy research named the Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center (UNM HSC), with aspirations to promote autophagy research locally, nationally, and internationally. The center has 3 major missions: (i) to support junior faculty in their endeavors to develop investigations in this area and obtain independent funding; (ii) to develop and provide technological platforms to advance autophagy research with emphasis on cellular approaches for high quality reproducible research; and (iii) to foster international collaborations through the formation of an International Council of Affiliate Members and through hosting national and international workshops and symposia. Scientifically, the AIM center is focused on autophagy and its intersections with other processes, with emphasis on both fundamental discoveries and applied translational research

    Autophagy in major human diseases

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    Abstract: Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy‐related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders
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