Proposed model for regulation of Aft1/2 in S. cerevisiae. Under iron replete conditions (left panel), the [2Fe-2S]-bridged Fra2-Grx3/4 complex (and possibly Fra1) relays the cellular iron status to Aft1/2, leading to Aft1/2 oligomerization. Aft1/2 is consequently shuttled to the cytosol by the exportin Msn5, deactivating the iron regulon. Under low iron conditions (right panel), Grx3/4 and Fra2 cannot bind an Fe-S cluster, and Aft1/2 does not receive the Fe-S signal. Msn5 does not recognize Aft1/2 and it accumulates in the nucleus where it activates the iron regulon.