Iron-dependent regulation of transferrin receptor expression in Trypanosoma brucei

Transferrin is an essential growth factor for African trypanosomes. Here we show that expression of the trypanosomal transferrin receptor, which bears no structural similarity with mammalian transferrin receptors, is regulate d by iron availability. Iron depletion of bloodstream forms of Trypanosoma brucei with the iron chelator deferoxamine resulted in a 3-fold up-regulati on of the transferrin receptor and a 3-fold increase of the transferrin upt ake rate. The abundance of expression site associated gene product 6 (ESAG6 ) mRNA, which encodes one of the two subunits of the trypanosome transferri n receptor, is regulated 5-fold by a post-transcriptional mechanism. In mam malian cells the stability of transferrin receptor mRNA is controlled by ir on regulatory proteins (IRPs) binding to iron-responsive elements (IREs) in the 3'-untranslated region (UTR). Therefore, the role of a T. brucei cytop lasmic aconitase (TbACO) that is highly related to mammalian IRP-1 was inve stigated. Iron regulation of the transferrin receptor was found to be unaff ected in Delta aco::NEO/Delta aco::HYG null mutants generated by targeted d isruption of the TbACO gene. Thus, the mechanism of posttranscriptional tra nsferrin receptor regulation in trypanosomes appears to be distinct from th e IRE/IRP paradigm. The transferrin uptake rate was also increased when try panosomes were transferred from medium supplemented with foetal bovine seru m to medium supplemented with sera from other vertebrates. Due to varying b inding affinities of the trypanosomal transferrin receptor for transferrins of different species, serum change can result in iron starvation. Thus, re gulation of transferrin receptor expression may be a fast compensatory mech anism upon transmission of the parasite to a new host species.