Drosophila HOPS and AP-3 Complex Genes Are Required for a Deltex-regulated Activation of Notch in the Endosomal Trafficking Pathway

Dev Cell. 2008 Nov;15(5):762-72. doi: 10.1016/j.devcel.2008.09.002.

Abstract

DSL ligands promote proteolysis of the Notch receptor, to release active Notch intracellular domain (N(ICD)). Conversely, the E3 ubiquitin ligase Deltex can activate ligand-independent Notch proteolysis and signaling. Here we show that Deltex effects require endocytic trafficking by HOPS and AP-3 complexes. Our data suggest that Deltex shunts Notch into an endocytic pathway with two possible endpoints. If Notch transits into the lysosome lumen, it is degraded. However, if HOPS and AP-3 deliver Notch to the limiting membrane of the lysosome, degradation of the Notch extracellular domain allows subsequent Presenilin-mediated release of N(ICD). This model accounts for positive and negative regulatory effects of Deltex in vivo. Indeed, we uncover HOPS/AP-3 contributions to Notch signaling during Drosophila midline formation and neurogenesis. We discuss ways in which these endocytic pathways may modulate ligand-dependent and -independent events, as a mechanism that can potentiate Notch signaling or dampen noise in the signaling network.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 3 / metabolism*
  • Animals
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / metabolism*
  • Endosomes / metabolism*
  • Membrane Proteins / metabolism*
  • Multiprotein Complexes
  • Protein Transport*
  • Receptors, Notch / metabolism

Substances

  • Adaptor Protein Complex 3
  • DX protein, Drosophila
  • Drosophila Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • N protein, Drosophila
  • Receptors, Notch