title: Drosophila GGA model: an ultimate gateway to GGA analysis.
abstract: Golgi-localized, γ-ear-containing, ADP ribosylation factor-binding (GGA) proteins are monomeric adaptors implicated in clathrin-mediated vesicular transport between the trans Golgi network and endosomes, characterized mainly from cell culture analysis of lysosomal sorting. To provide the first demonstration of GGA's role in vivo, we used Drosophila which has a single GGA and a single lysosomal sorting receptor, lysosomal enzyme receptor protein (LERP). Using RNAi knockdowns, we show that the Drosophila GGA is required for lysosomal sorting. We further identified authentic components of the Drosophila lysosomal sorting system--the sorting receptor LERP, the sorting adaptor GGA and the lysosomal cargo cathepsins B1, D and L--to show that GGA depletion results in lysosomal dysfunction. Abnormal lysosomal morphology, missorting of lysosomal cathepsins and impaired lysosomal proteolysis show disturbed LERP trafficking after GGA depletion. GGA is highly expressed in the mushroom bodies and the pigment cells of the retina, and increasing or decreasing the levels of GGA in the eyes leads to retinal defects. Reduced GGA levels also enhance an eye defect caused by overexpression of the autophagy-associated protein Blue cheese (Bchs), implicating GGA in autophagic processes. This shows that Drosophila provides an excellent whole-animal model to gain new insights into the function of GGA in the physiological environment of a multicellular organism.
authors.affiliation: Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Doisy Research Center, St. Louis, MO 63104, USA.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Eissenberg
authors.forename: Anne M
authors.initials: AM
authors.lastname: Ilvarsonn
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.forename: Abdul
authors.initials: A
authors.lastname: Waheed
authors.forename: Vladislav
authors.initials: V
authors.lastname: Krzyzanek
authors.forename: Regina
authors.initials: R
authors.lastname: Pohlmann
authors.forename: Daniela
authors.initials: D
authors.lastname: Waschkau
authors.forename: Doris
authors.initials: D
authors.lastname: Kretzschmar
authors.forename: André C
authors.initials: AC
authors.lastname: Dennes
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D012160:Retina / Q000378:metabolism; D022161:Transport Vesicles / Q000235:genetics / Q000378:metabolism*; D021601:trans-Golgi Network / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002966:Clathrin; D029721:Drosophila Proteins; C407306:GGA adaptor proteins; D051907:Lysosomal Membrane Proteins; D009419:Nerve Tissue Proteins; C472019:bchs protein, Drosophila; D002403:Cathepsins