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The lysosomal enzyme receptor protein (LERP) is not essential, but is implicated in lysosomal function in Drosophila

Medina Hasanagic1, Eline van Meel2, Shan Luan3

  • 1Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.

Biology Open
|September 26, 2015
PubMed

Insights

The lysosomal enzyme receptor protein (LERP) in fruit flies is crucial for lysosome function and autophagy, despite lacking the typical mannose 6-phosphate (Man 6-P) binding mechanism. Loss of LERP impairs lysosomal hydrolase levels and increases sensitivity to starvation.

Area of Science:

  • Cell Biology
  • Genetics
  • Biochemistry

Background:

  • The lysosomal enzyme receptor protein (LERP) in Drosophila melanogaster is homologous to the mammalian cation-independent mannose 6-phosphate (Man 6-P) receptor.
  • Mammalian receptors use the Man 6-P tag for lysosomal hydrolase trafficking, but Drosophila lack the enzymes for this modification, and LERP lacks conserved binding residues.

Purpose of the Study:

  • To investigate the function of LERP in lysosomal enzyme sorting and lysosome function in Drosophila.
  • To elucidate the role of LERP in the absence of the Man 6-P tagging system.

Main Methods:

  • RNA interference (RNAi)-mediated knockdown of LERP in Drosophila S2 cells.
  • Generation and analysis of a novel LERP null mutation (Lerp(F6)) in Drosophila.
  • Assessment of lysosomal hydrolase levels, cellular content, and secretion.
  • Evaluation of organismal phenotypes including viability, fertility, body weight, and response to dietary stress (chloroquine) and starvation.
  • Analysis of autophagy-related phenotypes, specifically an eye phenotype.

Main Results:

  • LERP depletion in S2 cells showed minimal impact on lysosomal hydrolase levels or secretion.
  • Lerp null mutant flies exhibited normal viability and fertility but reduced body weight.
  • Lerp mutants displayed a 30-40% reduction in several lysosomal hydrolases.
  • Mutant flies were hypersensitive to chloroquine and starvation, indicating impaired lysosome function.
  • Loss of LERP exacerbated an eye phenotype linked to defective autophagy.

Conclusions:

  • LERP plays a significant role in lysosome function and autophagy in Drosophila, independent of the canonical Man 6-P pathway.
  • The findings suggest LERP is involved in maintaining lysosomal homeostasis and autophagic processes in flies.
Keywords:
Drosophila sorting receptorLysosomal enzyme receptor proteinLysosomal sorting

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