Iron-dependent transcriptional regulation in Saccharomyces cerevisiae. (A) Activation of Aft1p under conditions of iron deprivation. The nuclear importin Pse1p mediates Aft1p translocation into the nucleus. Aft1p forms a complex with Grx3p and Grx4p, binds to DNA, and activates transcription. Although complex formation is not regulated by iron, it is not known whether complex formation occurs exclusively in the nucleus or also in the cytosol. “Coregulators” represent the numerous coactivators and corepressors that contribute to the regulation of the Aft1p regulon. These include the mediator complex, Snf1p/Snf4p, Ssn6, Nhp6p, Tup1, Hda1p, Cti6p, and heme. (B) Regulation of Aft1 activity under iron-replete conditions. Yfh1p, Grx5p, and glutathione are required for the production of ISC and the formation of an unknown compound that is a substrate for Atm1p. This compound is exported from mitochondria and may possibly be targeted to the nucleus. Under iron-replete conditions, Aft1p forms dimers that are recognized by the nuclear exportin Msn5p and lead to the accumulation of Aft1p in the cytosol. In a hypothetical model for the regulation of Aft1p, the production of the substrate for Atm1p is proportional to cellular iron levels. This substrate accumulates in the nucleus and leads to the dimerization of Aft1p, perhaps through the formation of a mixed disulfide bridge, and the complex is exported from the nucleus.

Response to iron deprivation in Saccharomyces cerevisiae. Proteins under the transcriptional control of Aft1p and Aft2p are labeled with black text. Ccc1p, proteins of the tricarboxylic acid cycle, the respiratory cytochromes, and the glutamate, heme, and biotin biosynthetic pathways are down-regulated during iron deficiency and are indicated with gray text.