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Published January 1, 1998 | public
Journal Article

The N-end rule pathway controls the import of peptides through degradation of a transcriptional repressor


Ubiquitin‐dependent proteolytic systems underlie many processes, including the cell cycle, cell differentiation and responses to stress. One such system is the N‐end rule pathway, which targets proteins bearing destabilizing N‐terminal residues. Here we report that Ubr1p, the main recognition component of this pathway, regulates peptide import in the yeast Saccharomyces cerevisiae through degradation of Cup9p, a 35 kDa homeodomain protein. Cup9p was identified using a screen for mutants that bypass the previously observed requirement for Ubr1p in peptide import. We show that Cup9p is a short‐lived protein (t_½ ∼5 min) whose degradation requires Ubr1p. Cup9p acts as a repressor of PTR2, a gene encoding the transmembrane peptide transporter. In contrast to engineered N‐end rule substrates, which are recognized by Ubr1p through their destabilizing N‐terminal residues, Cup9p is targeted by Ubr1p through an internal degradation signal. The Ubr1p‐Cup9p‐Ptr2p circuit is the first example of a physiological process controlled by the N‐end rule pathway. An earlier study identified Cup9p as a protein required for an aspect of resistance to copper toxicity in S.cerevisiae. Thus, one physiological substrate of the N‐end rule pathway functions as both a repressor of peptide import and a regulator of copper homeostasis.

Additional Information

© 1998 European Molecular Biology Organization. Received August 13, 1997; revised October 13, 1997; accepted October 14, 1997. We thank R.Deshaies, R.J.Dohmen, S.Grigoryev, M.Hochstrasser, S.Jentsch, E.S.Johnson, K.Madura, I.Ota and C.Trotta for the gifts of strains and plasmids; S.Carter for his guidance in the synthesis of Leu‐Eth; N.Johnsson, R.Deshaies, R.J.Dohmen and A.Webster for helpful discussions; L.Peck, Y.T.Kwon, A.Webster and F.Du for comments on the manuscript; S.Saha for help in overexpressing Cup9p; and N.Riley for technical assistance. This work was supported by grants to A.V. from the National Institutes of Health (DK39520 and GM31530).

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