TFR1 mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin. Since the number of TFR1 molecules at the cell surface is the rate-limiting step for iron entry into cells and is essential to prevent iron overload, TFR1 expression is precisely controlled at multiple levels. The latest advances in the molecular regulation of TFR1 expression and an understanding of TFR1 function beyond its canonical role in providing iron for erythroid precursors and rapidly proliferating cells has been reviewed (Gammella et al. 2017). Regulation of transferrin receptor trafficking by optineurin and its disease-associated mutants hsas been reviewed (Moharir et al. 2023).

The yeast manganese transporter, Smf1, is subject to two levels of regulation: heavy metal-induced sequestration in the cell and ubiquitination and degradation in the vacuole. Degradation requires Bsd2, a membrane protein with a PPxY motif that recruits the ubiquitin ligase Rsp5, and which plays a role in the quality control of membrane proteins that expose hydrophilic residues to the lipid bilayer. Stimpson et al. 2006 showed that degradation of Smf1 requires in addition one of a pair of related yeast proteins, Tre1 and Tre2, that also contain PPxY motifs. Tre1 can partially inhibit manganese uptake without Bsd2, but Bsd2 is required to induce Smf1 degradation. It has a relatively hydrophilic transmembrane domain and binds to Bsd2. Possibly, the Tre proteins specifically link Smf1 to the Bsd2-dependent quality control system. Their luminal domains are related to the transferrin receptor, but these are dispensable for Smf1 regulation (Stimpson et al. 2006).

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