Alternative mechanisms of Notch activation by partitioning into distinct endosomal domains

Hideyuki Shimizu, Samira Hosseini Alghaderi, Simon Woodcock, Baron Martin

Research output: Contribution to journalArticlepeer-review

Abstract

Different membrane microdomain compositions provide unique environments that can regulate signaling receptor function. We identify microdomains on the endosome membrane of Drosophila endosomes, enriched in lipid-raft or clathrin/ESCRT-0, which are associated with Notch activation by distinct, ligand-independent mechanisms. Transfer of Notch between microdomains is regulated by Deltex and Suppressor of deltex ubiquitin ligases and is limited by a gate-keeper role for ESCRT complexes. Ubiquitination of Notch by Deltex recruits it to the clathrin/ESCRT-0 microdomain and enhances Notch activation by an ADAM10-independent/TRPML-dependent mechanism. This requirement for Deltex is bypassed by the downregulation of ESCRT-III. In contrast, while ESCRT-I depletion also activates Notch, it does so by an ADAM10-dependent/TRPML-independent mechanism and Notch is retained in the lipid raft-like microdomain. In the absence of such endosomal perturbation, different activating Notch mutations also localize to different microdomains and are activated by different mechanisms. Our findings demonstrate the interplay between Notch regulators, endosomal trafficking components, and Notch genetics, which defines membrane locations and activation mechanisms.
Original languageEnglish
JournalJournal of Cell Biology
Volume223
Issue number5
Early online date15 Feb 2024
DOIs
Publication statusPublished - 1 Jun 2024

Keywords

  • ADAM10 Protein/metabolism
  • Animals
  • Clathrin/metabolism
  • Down-Regulation
  • Drosophila
  • Drosophila Proteins/metabolism
  • Endosomal Sorting Complexes Required for Transport/metabolism
  • Endosomes/metabolism
  • Membrane Microdomains/metabolism
  • Membrane Proteins/metabolism
  • Receptors, Notch/metabolism
  • Transient Receptor Potential Channels
  • Ubiquitination

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