Proposed modes of action of BTSL and BTS in Fe homeostasis. (A) The transcription of FIT is up-regulated under Fe deficiency (top), resulting in increased levels of FIT protein, which forms a dimer with bHLH39 (or bHLH38). The FIT + bHLH39 dimer up-regulates the transcription of genes for Fe uptake, including IRT1 and FRO2. The transcript levels of BTSL2 are also controlled by FIT. The BTSL proteins act as E3 ubiquitin ligases and promote the degradation of FIT. Iron binding to the N-terminal hemerythrin domains of BTSL is likely to affect their stability and forms another layer of regulation. The constant turnover of FIT is proposed to facilitate rapid down-regulation of the Fe deficiency response when Fe becomes available. (B) BTSL1 and BTSL2 (orange) are expressed primarily in the epidermis and cortex cells, where they regulate the level of FIT protein. BTS (green) is predominantly expressed in the stele and shoot, and regulates the levels of ILR3. Thus, BTSL proteins provide a first protection mechanism against Fe overload outside the endodermis and Casparian strip, whereas BTS protects against Fe overload inside this barrier for nutrients.