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. Although 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.
Xia
Zanxian
Z
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Turner
Glenn C
GC
Hwang
Cheol-Sang
CS
Byrd
Christopher
C
Varshavsky
Alexander
A
D000495:Allosteric Site; D000596:Amino Acids / Q000378:metabolism*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry*; D008954:Models, Biological; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000596:Amino Acids; C090457:CUP9 protein, S cerevisiae; C065455:CYC8 protein, S cerevisiae; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009687:Nuclear Proteins; C093495:PTR2 protein, S cerevisiae; C106976:PTR3 protein, S cerevisiae; D012097:Repressor Proteins; C120527:SSY1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C066502:TUP1 protein, S cerevisiae; D014157:Transcription Factors; C066066:UBR1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases