Copper ion-sensing transcription factor Mac1p post-translationally controls the degradation of its target gene product Ctr1p.
Copper ion uptake must be regulated to avoid both deficiency and excess because its essential yet toxic biological nature depends on the concentration. Yeast copper uptake is controlled at both the transcriptional and post-translational levels. The transcription of CTR1 and CTR3, encoding high affinity copper ion transporters, is regulated by the copper ion-sensing transcription factor Mac1p through the cis-acting copper ion-responsive elements in CTR1 and CTR3 promoters. Ctr1p is known to undergo degradation in cells exposed to high copper levels. We report that Mac1p is also required for copper-dependent Ctr1p degradation. Both mutations within a conserved copper ion binding motif, the "Cu-fist" in the Mac1p DNA-binding domain, and within a metal ion binding motif, REP-III located in the cytosolic domain of Ctr1p, cause defects in Ctr1p turnover. Furthermore, we show that the Mac1p limits intracellular copper accumulation likely by controlling Ctr1p degradation. The findings have uncovered an unprecedented mechanism by which a transcription factor not only regulates its target gene transcription but also controls the degradation of its target gene product.
Yonkovich
Jesse
J
Department of Environmental Toxicology, University of California, Santa Cruz, California 95064, USA.
McKenndry
Roslyn
R
Shi
Xiaoli
X
Zhu
Zhiwu
Z
D001483:Base Sequence; D027682:Cation Transport Proteins; D003300:Copper / Q000378:metabolism; D000079923:Copper Transporter 1; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C490078:CTR1 protein, S cerevisiae; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C084954:MAC1 protein, S cerevisiae; D008565:Membrane Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D003300:Copper