Ubiquitination and endocytosis of plasma membrane proteins: Role of Nedd4/Rsp5p family of ubiquitin-protein ligases

In addition to its well-known role in recognition by the proteasome, ubiqui tin-conjugation is also involved in downregulation of membrane receptors, t ransporters and channels. In most cases, ubiquitination of these plasma mem brane proteins leads to their internalization followed by targeting to the lysosome/vacuole for degradation. A crucial role in ubiquitination of many plasma membrane proteins appears to be played by ubiquitin-protein ligases of the Nedd4/Rsp5p family. All family members carry an N-terminaI Ca2+-depe ndent lipid/protein binding (C2) domain, two to four WW domains and a C-ter minal catalytic Hect-domain. Nedd4 is involved in downregulation of the epi thelial Na+ channel, by binding of its WW domains to specific PY motifs of the channel. Rsp5p, the unique family member in S. cerevisiae, is involved in ubiquitin-dependent endocytosis of a great number of yeast plasma membra ne proteins. These proteins lack apparent PY motifs, but carry acidic seque nces, and/or phosphorylated-based sequences that might be important, direct ly or indirectly, for their recognition by Rsp5p. In contrast to polyubiqui tination leading to proteasomal recognition, a number of Rsp5p targets carr y few ubiquitins per protein, and moreover with a different ubiquitin linka ge. Accumulating evidence suggests that, at least in yeast, ubiquitin itsel f may constitute an internalization signal, recognized by a hypothetical re ceptor, Recent data also suggest that Nedd4/Rsp5p might play a role in the endocytic process possibly involving its C2 domain, in addition to its role in ubiquitinating endocytosed proteins.