Article abstract
Nature Cell Biology 8, 124 - 136 (2006)
Published online: 15 January 2006 | doi:10.1038/ncb1348
V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway
Andrés Hurtado-Lorenzo1, Mhairi Skinner2, Jaafar El Annan1, Masamitsu Futai3, Ge-Hong Sun-Wada4, Sylvain Bourgoin5, James Casanova6, Alan Wildeman2, Shaliha Bechoua1, Dennis A. Ausiello1, Dennis Brown1 & Vladimir Marshansky1
Abstract
The recruitment of the small GTPase Arf6 and ARNO from cytosol to endosomal membranes is driven by V-ATPase-dependent intra-endosomal acidification. The molecular mechanism that mediates this pH-sensitive recruitment and its role are unknown. Here, we demonstrate that Arf6 interacts with the c-subunit, and ARNO with the a2-isoform of V-ATPase. The a2-isoform is targeted to early endosomes, interacts with ARNO in an intra-endosomal acidification-dependent manner, and disruption of this interaction results in reversible inhibition of endocytosis. Inhibition of endosomal acidification abrogates protein trafficking between early and late endosomal compartments. These data demonstrate the crucial role of early endosomal acidification and V-ATPase/ARNO/Arf6 interactions in the regulation of the endocytic degradative pathway. They also indicate that V-ATPase could modulate membrane trafficking by recruiting and interacting with ARNO and Arf6; characteristics that are consistent with the role of V-ATPase as an essential component of the endosomal pH-sensing machinery.
- Program in Membrane Biology & Nephrology Division, Richard Simches Research Center, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada, N1G 2W1.
- Futai Special Laboratory, Microbial Chemistry Research Center, Shinagawa, Tokyo 141-0021, Japan.
- Department of Biochemistry, Doshisha Women's College, Kyoto 610-0395, Japan.
- CHUL, Université Laval, Sainte-Foy, Québec, Canada, G1V 4G2.
- Department of Cell Biology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
Correspondence to: Vladimir Marshansky1 e-mail: Vladimir_Marshansky@hms.harvard.edu
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