Human Molecular Genetics Advance Access first published online on October 28, 2009
This version [Corrected Proof] published online on November 11, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp490
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Consortin, a trans-Golgi network cargo receptor for the plasma membrane targeting and recycling of connexins
1 Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, 75724 Paris, France, 2 INSERM UMRS 587, 75724 Paris, France, 3 Unidad de Genética Molecular, Hospital Ramón y Cajal, 28034 Madrid, Spain, 4 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28034 Madrid, Spain, 5 Université Pierre & Marie Curie, 75006 Paris, France, 6 Department of Cell Physiology and Metabolism, University of Geneva School of Medicine, 1211 Geneva 04, Switzerland, 7 Molecular Diagnostics Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 8 Institut Curie, Centre de Recherche, UMR 144, 75248 Paris, France, 9 CNRS, UMR 144, 75248 Paris, France and 10 Chaire de Génétique et Physiologie Cellulaire, Collège de France, 75231 Paris, France
* To whom correspondence should be addressed at: Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France. Tel: +33 145688890; Fax: +33 140613442; Email: christine.petit{at}pasteur.fr
Received September 25, 2009; Accepted October 22, 2009
Targeting of numerous transmembrane proteins to the cell surface is thought to depend on their recognition by cargo receptors that interact with the adaptor machinery for anterograde traffic at the distal end of the Golgi complex. We report here on consortin, a novel integral membrane protein that is predicted to be intrinsically disordered, i.e. that contains large segments whose native state is unstructured. We identified consortin as a binding partner of connexins, the building blocks of gap junctions. Consortin is located at the trans-Golgi network (TGN), in tubulovesicular transport organelles, and at the plasma membrane. It directly interacts with the TGN clathrin adaptors GGA1 and GGA2, and disruption of this interaction by expression of a consortin mutant lacking the acidic cluster–dileucine (DXXLL) GGA interaction motif causes an intracellular accumulation of several connexins. RNA interference-mediated silencing of consortin expression in HeLa cells blocks the cell surface targeting of these connexins, which accumulate intracellularly, whereas partial depletion and redistribution of the consortin pool slows down the intracellular degradation of gap junction plaques. Altogether, our results show that, by studying connexin trafficking, we have identified the first TGN cargo receptor for the targeting of transmembrane proteins to the plasma membrane. The identification of consortin provides in addition a potential target for therapies aimed at diseases in which connexin traffic is altered, including cardiac ischemia, peripheral neuropathies, cataracts and hearing impairment.
Sequence accession numbers. GenBank: Human CNST cDNA, NM_152609 [GenBank] ; mouse Cnst cDNA, NM_146105 [GenBank] .
Present address: INSERM U840, Collège de France, 75231 Paris, France.