title: Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.
abstract: Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power of contraction. Little is known about how T-tubules maintain highly organized structures and contacts throughout the contractile system despite the ongoing muscle remodeling that occurs with muscle atrophy, damage and aging. We uncovered an essential role for autophagy in T-tubule remodeling with genetic screens of a developmentally regulated remodeling program in Drosophila abdominal muscles. Here, we show that autophagy is both upregulated with and required for progression through T-tubule disassembly stages. Along with known mediators of autophagosome-lysosome fusion, our screens uncovered an unexpected shared role for Rab2 with a broadly conserved function in autophagic clearance. Rab2 localizes to autophagosomes and binds to HOPS complex members, suggesting a direct role in autophagosome tethering/fusion. Together, the high membrane flux with muscle remodeling permits unprecedented analysis both of T-tubule dynamics and fundamental trafficking mechanisms.
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.|Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
authors.forename: Naonobu
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
authors.forename: Wilson
authors.initials: W
authors.lastname: Huang
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
authors.forename: Tzu-Han
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Groulx
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Jean
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
authors.forename: Jen
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kuchitsu
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Koyama-Honda
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Noboru
authors.identifier: 0000-0002-6258-6444
authors.initials: N
authors.lastname: Mizushima
authors.affiliation: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
authors.forename: Mitsunori
authors.identifier: 0000-0002-8620-5853
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
authors.forename: Amy A
authors.identifier: 0000-0003-4300-176X
authors.initials: AA
authors.lastname: Kiger
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion; D009024:Morphogenesis / Q000235:genetics*; D009132:Muscles / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050600:SNARE Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020693:rab2 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: C527373:Atg8a protein, Drosophila; D029721:Drosophila Proteins; D020033:Protein Isoforms; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D034741:RNA, Small Interfering; D050600:SNARE Proteins; C582206:Snap29 protein, Drosophila; C582207:VAMP7 protein, Drosophila; D000090802:rab7 GTP-Binding Proteins; D020691:rab GTP-Binding Proteins; D020693:rab2 GTP-Binding Protein
keywords: Drosophila metamorphosis; Rab GTPase; T-tubule; autophagosome-lysosome fusion; autophagy; cell biology; developmental biology; muscle fiber; stem cells