The role of Nedd4/Nedd4-like dependant ubiquitylation in epithelial transport processes

Pflugers Arch. 2003 Jun;446(3):334-8. doi: 10.1007/s00424-003-1027-x. Epub 2003 Apr 16.

Abstract

Ubiquitylation has emerged as an important mechanism for controlling surface expression of membrane proteins. This post-translational modification involves the sequential action of several enzymes including a ubiquitin-activating enzyme E1, a ubiquitin-conjugating enzyme E2 and a ubiquitin-protein ligase E3. E3s are responsible for substrate recognition. Here we describe the role of the Nedd4/Nedd4-like family of ubiquitin-protein ligases in the regulation of proteins involved in epithelial transport. The Nedd4/Nedd4-like proteins are composed of a N-terminal C2 domain, several WW domains and a catalytic HECT domain. The epithelial Na(+) channel ENaC is the best studied example of a Nedd4/Nedd4-like substrate. Its cell surface expression is regulated by the ubiquitin-protein ligase Nedd4-2 via direct PY motif/WW domain interaction. This regulatory mechanism is impaired in Liddle's disease, an inherited form of human hypertension, and is controlled by Sgk1, an aldosterone-inducible kinase which phosphorylates Nedd4-2. The regulation of ENaC by Nedd4-2 is a paradigm for the control of epithelial membrane proteins, as evidenced by the regulation of the ClC-5 chloride channel by the ubiquitin-protein ligase WWP2 or the tight junction protein Occludin by Itch.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biological Transport / physiology
  • Chloride Channels / metabolism
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Humans
  • Membrane Proteins / metabolism
  • Nedd4 Ubiquitin Protein Ligases
  • Occludin
  • Sodium Channels / metabolism*
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / physiology*

Substances

  • CLC-5 chloride channel
  • Chloride Channels
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Membrane Proteins
  • OCLN protein, human
  • Occludin
  • Sodium Channels
  • Ubiquitin
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Nedd4L protein, human
  • Ubiquitin-Protein Ligases