Fig. 8: Model for the natural function and physiological role of PfCRT.

PfCRT transports host-derived peptides 4–11 residues in length, and of varying composition and charge, out of the DV and into the parasite’s cytosol. Wild-type PfCRT transports a broader range of peptides, and has a higher capacity for peptide transport, than most CQ-resistance-conferring isoforms of PfCRT. The diminished abilities of the mutant transporters to efflux peptides results in the accumulation of these peptides within CQ-resistant parasites. Moreover, the promiscuous degradation of the accumulated peptides leads to the build-up of small peptide fragments and amino acids, which exerts further osmotic pressure upon the DV and causes feedback inhibition of the digestion of host proteins. PfCRT therefore serves two roles: (1) it prevents osmotic stress of the DV by exporting peptides and (2) it delivers these peptides to the cytosol where they are degraded into amino acids to fuel parasite growth. AAT1: amino acid transporter 1.