title: The lysosomal enzyme receptor protein (LERP) is not essential, but is implicated in lysosomal function in Drosophila melanogaster.
abstract: The lysosomal enzyme receptor protein (LERP) of Drosophila melanogaster is the ortholog of the mammalian cation-independent mannose 6-phosphate (Man 6-P) receptor, which mediates trafficking of newly synthesized lysosomal acid hydrolases to lysosomes. However, flies lack the enzymes necessary to make the Man 6-P mark, and the amino acids implicated in Man 6-P binding by the mammalian receptor are not conserved in LERP. Thus, the function of LERP in sorting of lysosomal enzymes to lysosomes in Drosophila is unclear. Here, we analyze the consequence of LERP depletion in S2 cells and intact flies. RNAi-mediated knockdown of LERP in S2 cells had little or no effect on the cellular content or secretion of several lysosomal hydrolases. We generated a novel Lerp null mutation, Lerp(F6), which abolishes LERP protein expression. Lerp mutants have normal viability and fertility and display no overt phenotypes other than reduced body weight. Lerp mutant flies exhibit a 30-40% decrease in the level of several lysosomal hydrolases, and are hypersensitive to dietary chloroquine and starvation, consistent with impaired lysosome function. Loss of LERP also enhances an eye phenotype associated with defective autophagy. Our findings implicate Lerp in lysosome function and autophagy.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Medina
authors.initials: M
authors.lastname: Hasanagic
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Eline
authors.initials: E
authors.lastname: van Meel
authors.affiliation: Department of Biology, Saint Louis University, St. Louis, MO 63103, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Luan
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Aurora
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Kornfeld
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA eissenjc@slu.edu.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Eissenberg
keywords: Drosophila sorting receptor; Lysosomal enzyme receptor protein; Lysosomal sorting