Ubiquitin-mediated internalization of connexin43 is independent of the canonical endocytic tyrosine-sorting signal.

Gap junctions are specialized cell-cell contacts that provide direct intercellular communication between eukaryotic cells. The tyrosine-sorting signal (YXXO), present at amino acids 286-289 of Cx43 (connexin43), has been implicated in the internalization of the protein. In recent years, ubiquitination of Cx43 has also been proposed to regulate gap junction intercellular ...
communication; however, the underlying mechanism and molecular players involved remain elusive. In the present study, we demonstrate that ubiquitinated Cx43 is internalized through a mechanism that is independent of the YXXO signal. Indeed, expression of a Cx43-Ub (ubiquitin) chimaera was shown to drive the internalization of a mutant Cx43 in which the YXXO motif was eliminated. Immunofluorescence, cycloheximide-chase and cell-surface-protein biotinylation experiments demonstrate that oligomerization of Cx43-Ub into hemichannels containing wild-type Cx43 or mutant Cx43Y286A is sufficient to drive the internalization of the protein. Furthermore, the internalization of Cx43 induced by Cx43-Ub was shown to depend on its interaction with epidermal growth factor receptor substrate 15.
Mesh Terms:
Animals, COS Cells, Cell Communication, Cercopithecus aethiops, Connexin 43, Gap Junctions, Gene Knockdown Techniques, HEK293 Cells, Humans, Mice, Rabbits, Rats, Recombinant Fusion Proteins, Ubiquitin, Ubiquitination
Biochem. J.
Date: Jul. 15, 2011
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