title: Atg6/UVRAG/Vps34-containing lipid kinase complex is required for receptor downregulation through endolysosomal degradation and epithelial polarity during Drosophila wing development.
abstract: Atg6 (Beclin 1 in mammals) is a core component of the Vps34 PI3K (III) complex, which promotes multiple vesicle trafficking pathways. Atg6 and Vps34 form two distinct PI3K (III) complexes in yeast and mammalian cells, either with Atg14 or with UVRAG. The functions of these two complexes are not entirely clear, as both Atg14 and UVRAG have been suggested to regulate both endocytosis and autophagy. In this study, we performed a microscopic analysis of UVRAG, Atg14, or Atg6 loss-of-function cells in the developing Drosophila wing. Both autophagy and endocytosis are seriously impaired and defective endolysosomes accumulate upon loss of Atg6. We show that Atg6 is required for the downregulation of Notch and Wingless signaling pathways; thus it is essential for normal wing development. Moreover, the loss of Atg6 impairs cell polarity. Atg14 depletion results in autophagy defects with no effect on endocytosis or cell polarity, while the silencing of UVRAG phenocopies all but the autophagy defect of Atg6 depleted cells. Thus, our results indicate that the UVRAG-containing PI3K (III) complex is required for receptor downregulation through endolysosomal degradation and for the establishment of proper cell polarity in the developing wing, while the Atg14-containing complex is involved in autophagosome formation.
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Budapest 1117, Hungary.
authors.forename: Péter
authors.identifier: 0000-0001-7374-667X
authors.initials: P
authors.lastname: Lőrincz
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Budapest 1117, Hungary.
authors.forename: Zsolt
authors.identifier: 0000-0003-1900-3167
authors.initials: Z
authors.lastname: Lakatos
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Budapest 1117, Hungary.
authors.forename: Tamás
authors.identifier: 0000-0001-8142-3221
authors.initials: T
authors.lastname: Maruzs
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Budapest 1117, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Szatmári
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Budapest 1117, Hungary.
authors.forename: Viktor
authors.identifier: 0000-0003-1316-7013
authors.initials: V
authors.lastname: Kis
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Budapest 1117, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Sass
mesh_terms: D000818:Animals; D001343:Autophagy; D000071186:Beclin-1; D016764:Cell Polarity; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D008247:Lysosomes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011679:Pupa / Q000648:ultrastructure; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development* / Q000648:ultrastructure
chemical_list: C580769:Atg6 protein, Drosophila; D000071186:Beclin-1; D029721:Drosophila Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; C561319:UVRAG protein, Drosophila; D033921:Vesicular Transport Proteins; D019869:Phosphatidylinositol 3-Kinases