Notch ligand ubiquitylation: what is it good for?

Abstract

In the first volume of Developmental Cell, it was reported that the classic Drosophila neurogenic gene neuralized encodes a ubiquitin ligase that monoubiquitylates the Notch ligand Delta, thus promoting Delta endocytosis. A requirement for ligand internalization by the signal-sending cell, although counterintuitive, remains to date a feature unique to Notch signaling. Ten years and many ubiquitin ligases later, we discuss sequels to these three papers with an eye toward reviewing the development of ideas for how ligand ubiquitylation and endocytosis propel Notch signaling.

Figure. Schematic of proposed routes and outcomes for Neur/Mib-dependent ligand endocytosis

Step 1: Ligand delivered to the cell surface is ubiquitylated by either Mib or Neur, which facilitates interactions with the endocytic adaptor epsin to promote ligand endocytosis. Following internalization, ligand delivered to the early endosome enters the recycling endosome from which it is returned to the plasma membrane. In this scenario, Neur-mediated ubiquitylation serves as a signal for ligand transcytosis to a specific micro-domain conducive to signaling. Step 2: The critical role of ligand endocytosis is to exert a pulling force on the Notch receptor in adjacent cells. To overcome resistance to endocytosis of ligand bound to Notch on an adjacent cell, ligand is proposed to harness mechanical force inherent to endocytosis to dissociate the Notch extracellular domain (NECD) from the intact Notch heterodimer. Internalization of ligand-bound NECD exposes the remaining membrane-associated Notch to activating proteolysis, first by ADAM followed by γ-secretase to release the Notch intracellular domain (NICD) that moves to the nucleus to directly participate in transcription of Notch target genes.