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Vol. 18, Issue 5, 1790-1802, May 2007

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GGA2- and Ubiquitin-dependent Trafficking of Arn1, the Ferrichrome Transporter of Saccharomyces cerevisiae

Youngwoo Kim^*,, Yi Deng^*, and Caroline C. Philpott

Genetics and Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Submitted September 26, 2006; Revised January 18, 2007; Accepted February 28, 2007
Monitoring Editor: David Drubin

The intracellular trafficking of Arn1, a ferrichrome transporter in Saccharomyces cerevisiae, is controlled in part by the binding of ferrichrome to the transporter. In the absence of ferrichrome, Arn1 is sorted directly from the Golgi to endosomes. Ferrichrome binding triggers the redistribution of Arn1 to the plasma membrane, whereas ferrichrome transport is associated with the cycling of Arn1 between the plasma membrane and endosomes. Here, we report that the clathrin adaptor Gga2 and ubiquitination by the Rsp5 ubiquitin ligase are required for trafficking of Arn1. Gga2 was required for Golgi-to-endosomal trafficking of Arn1, which was sorted from endosomes to the vacuole for degradation. Trafficking into the vacuolar lumen was dependent on ubiquitination by Rsp5, but ubiquitination was not required for plasma membrane accumulation of Arn1 in the presence of ferrichrome. Retrograde trafficking via the retromer complex or Snx4 was also not required for plasma membrane accumulation. High concentrations of ferrichrome led to higher levels of ubiquitination of Arn1, but they did not induce degradation. Without this ubiquitination, Arn1 remained on the plasma membrane, where it was active for transport. Arn1 was preferentially modified with polyubiquitin chains on a cluster of lysine residues at the amino terminus of the transporter.

* These authors contributed equally to this work.

Present address: Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Georgetown University, Washington, DC.

Address correspondence to: Caroline C. Philpott (carolinep{at}intra.niddk.nih.gov).

Abbreviations used: FC, ferrichrome; MVB, multivesicular body; TGN, trans-Golgi network; Ub, ubiquitin.

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