The knock-down of the chloroquine resistance transporter PfCRT is linked to oligopeptide handling in Plasmodium falciparum

The chloroquine resistance transporter, PfCRT, is an essential factor
during intraerythrocytic development of the human malaria parasite
Plasmodium falciparum. PfCRT resides at the digestive vacuole of the
parasite, where hemoglobin taken up by the parasite from its host cell is
degraded. PfCRT can acquire several mutations that render PfCRT a drug
transporting system expelling compounds targeting hemoglobin degradation
from the digestive vacuole. The non-drug related function of PfCRT is less
clear, although a recent study has suggested a role in oligopeptide
transport based on studies conducted in a heterologous expression system.
The uncertainty about the natural function of PfCRT is partly due to a
lack of a null mutant and a dearth of functional assays in the parasite.
Here, we report on the generation of a conditional PfCRT knock-down mutant
in P. falciparum. The mutant accumulated oligopeptides 2 to at least 8
residues in length under knock-down conditions, as shown by comparative
global metabolomics. The accumulated oligopeptides were structurally
diverse, had an isoelectric point between 4.0 and 5.4 and were
electrically neutral or carried a single charge at the digestive vacuolar
pH of 5.2. Fluorescently-labeled dipeptides and live cell imaging
identified the digestive vacuole as the compartment where oligopeptides
accumulated. Our findings suggest a function of PfCRT in oligopeptide
transport across the digestive vacuolar membrane in P. falciparum and
associated with it a role in nutrient acquisition and the maintenance of
the colloid osmotic balance.