The role of Nedd4/Nedd4-like dependant ubiquitylation in epithelial transport processes.
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.
Flores
Sandra Y
SY
Institute of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland.
Debonneville
Christophe
C
Staub
Olivier
O
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D018118:Chloride Channels / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D062793:Occludin; D015222:Sodium Channels / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
C097503:CLC-5 chloride channel; D018118:Chloride Channels; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D015222:Sodium Channels; D025801:Ubiquitin; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases