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Published October 24, 2008 | Published + Accepted Version
Journal Article Open

Amino acids induce peptide uptake via accelerated degradation of CUP9, the transcriptional repressor of the PTR2 peptide transporter


Multiple pathways link expression of PTR2, the transporter of di- and tripeptides in the yeast Saccharomyces cerevisiae, to the availability and quality of nitrogen sources. Previous work has shown that induction of PTR2 by extracellular amino acids requires, in particular, SSY1 and PTR3. SSY1 is structurally similar to amino acid transporters, but functions as a sensor of amino acids. PTR3 acts downstream of SSY1. Expression of the PTR2 peptide transporter is induced not only by amino acids but also by dipeptides with destabilizing N-terminal residues. These dipeptides bind to UBR1, the ubiquitin ligase of the N-end rule pathway, and allosterically accelerate the UBR1-dependent degradation of CUP9, a transcriptional repressor of PTR2. UBR1 targets CUP9 through its internal degron. Here we demonstrate that the repression of PTR2 by CUP9 requires TUP1 and SSN6, the corepressor proteins that form a complex with CUP9. We also show that the induction of PTR2 by amino acids is mediated by the UBR1-dependent acceleration of CUP9 degradation that requires both SSY1 and PTR3. The acceleration of CUP9 degradation is shown to be attained without increasing the activity of the N-end rule pathway toward substrates with destabilizing N-terminal residues. We also found that GAP1, a general amino acid transporter, strongly contributes to the induction of PTR2 by Trp. While several aspects of this complex circuit remain to be understood, our findings establish new functional links between the amino acids-sensing SPS system, the CUP9-TUP1-SSN6 repressor complex, the PTR2 peptide transporter and the UBR1-dependent N-end rule pathway.

Additional Information

© 2008 the American Society for Biochemistry and Molecular Biology. Received for publication, May 26, 2008 , and in revised form, July 14, 2008. Originally published In Press as doi:10.1074/jbc.M803980200 on August 15, 2008. We thank R.J. Deshaies (California Institute of Technology, Pasadena, CA), B. André (Université Libre de Bruxelles, Belgium), M.C. Kielland-Brandt (Carlsberg Laboratory, Copenhagen, Denmark), and C. Wittenberg (Scripps Research Institute, La Jolla, CA) for S. cerevisiae strains, R. Zitomer (State University of New York, Albany, NY) for the SSN6-expressing plasmid, and A. Sil (University of California, San Francisco, CA) for the pAS315 plasmid. We are grateful to former and current members of the Varshavsky laboratory for helpful discussions and comments on the manuscript. This work was supported, in whole or in part, by National Institutes of Health Grants DK39520 and GM31530 (to A.V.). This work was also supported by the Sandler Program for Asthma Research, and from the Ellison Medical Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Published - XIAjbc08b.pdf

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