Regulation of PfEMP1–VAR2CSA translation by a Plasmodium translation-enhancing factor

Abstract

Pregnancy-associated malaria commonly involves the binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate A (CSA) through the PfEMP1-VAR2CSA protein. VAR2CSA is translationally repressed by an upstream open reading frame. In this study, we report that the P. falciparum translation enhancing factor (PTEF) relieves upstream open reading frame repression and thereby facilitates VAR2CSA translation. VAR2CSA protein levels in var2csa-transcribing parasites are dependent on the expression level of PTEF, and the alleviation of upstream open reading frame repression requires the proteolytic processing of PTEF by PfCalpain. Cleavage generates a C-terminal domain that contains a sterile-alpha-motif-like domain. The C-terminal domain is permissive to cytoplasmic shuttling and interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence. It also enhances translation in a heterologous translation system and thus represents the first non-canonical translation enhancing factor to be found in a protozoan. Our results implicate PTEF in regulating placental CSA binding of infected erythrocytes.

Enzymatic Synthesis of Homogeneous Chondroitin Sulfate Oligosaccharides

“…CSs are known to be involved in cancer metastasis [1] , parasitic infections [2] and neuron growth inhibition after injury [3] . The sulfation patterns in CS dictate the binding affinity to the protein targets to manifest the selectivity in biological functions [4] .…”

“…The sulfation patterns in CS dictate the binding affinity to the protein targets to manifest the selectivity in biological functions [4] . A 6- O -sulfated N -acetyl galactosamine (GalNAc6S) containing CS facilitates the infection of B. burgdorferi to cause lyme disease [5] , and 4- O -sulfated N -acetyl galactosamine (GalNAc4S) involves in P. falciparum infection that causes malaria [2a] . A domain containing 4,6 disulfated N -acetyl galactosamine (GalNAc4S6S) residues is proved to be necessary to direct neuronal signaling and inhibit axon growth [3c, 6] .…”

Messenger RNAs with large numbers of upstream ORFs are translated via leaky scanning and reinitiation in the asexual stages ofPlasmodium falciparum

“…Results shown so far have indicated that P. falciparum parasites, despite having multiple uAUGs/uORFs in the 5 leaders of their mRNAs, are able to translate their CDS by leaky scanning to bypass weak Kozak sequences and by reinitiation at the dORF. Reinitiation has been described previously in P. falciparum for translation of the var2csa gene in the presence of a 360 nucleotide long uORF (Chan et al, 2017), with a parasite translation factor, PTEF, being induced in parasites that are found in the placenta of pregnant women having malaria. Our data show that reinitiation may occur frequently in asexual parasites as well.…”

“…Indeed, a member of the var gene family, the var2csa gene, also has an uORF with a Kozak sequence having 'G' at the +4 position and this uORF plays a role translational repression of the dORF (Chan et al, 2017).…”

Translational Control in the Latency of Apicomplexan Parasites

“…Experimentally validated uORFs remain unexplored in Toxoplasma and only two examples have been seen in Plasmodium to date, one in the 5′ leader encoded in the var2csa variant of the PfEMP1 gene family and another within gene of unknown function [58,59]. The signal that promotes var2csa protein production remains elusive but its translation involves ribosome reinitiation after uORF translation and is associated with a Plasmodium -specific translation enhancing factor that binds ribosomes, suggesting that changes to the translational machinery permit altered functionality [60,61]. …”