Plasmodium falciparum translational machinery condones polyadenosine repeats

Abstract

Plasmodium falciparum is a causative agent of human malaria. Sixty percent of mRNAs from its extremely AT-rich (81%) genome harbor long polyadenosine (polyA) runs within their ORFs, distinguishing the parasite from its hosts and other sequenced organisms. Recent studies indicate polyA runs cause ribosome stalling and frameshifting, triggering mRNA surveillance pathways and attenuating protein synthesis. Here, we show that P. falciparum is an exception to this rule. We demonstrate that both endogenous genes and reporter sequences containing long polyA runs are efficiently and accurately translated in P. falciparum cells. We show that polyA runs do not elicit any response from No Go Decay (NGD) or result in the production of frameshifted proteins. This is in stark contrast to what we observe in human cells or T. thermophila, an organism with similar AT-content. Finally, using stalling reporters we show that Plasmodium cells evolved not to have a fully functional NGD pathway.

TheGiardia lambliaribosome structure reveals divergence in translation and quality control pathways

“…Interestingly, when we examined the G. lamblia genome for proteins involved in NGD and RQC, we were unable to identify orthologs for several key proteins, including Listerin and GIGYF2, in G. lamblia and other protists (Figure 4C). Given the recent report that classic NGD substrates fail to elicit decay in P. falciparum (Pavlovic-Djuranovic et al, 2020), our results raise the idea that this pathway is surprisingly plastic throughout eukaryotic evolution and the implications warrant further investigation.…”

“…Surveillance machinery then recognizes the interface between the two collided ribosomes, triggering destruction of the transcript and nascent peptides. Notably, a recent report indicates that another protist, Plasmodium falciparum , fails to recognize classic no-go decay substrates, raising the question of whether other protists might also lack this surveillance pathway (Pavlovic-Djuranovic et al, 2020). However, with the ribosome structure from G. lamblia and many other protozoa species unsolved (Figure 1A), these possibilities remain unexplored.…”

Functional characterization of 5′ UTR cis-acting sequence elements that modulate translational efficiency in Plasmodium falciparum and humans

“…Among eukaryotes, P. falciparum presents several distinct features that bear upon translation. First, the AT-rich genome contains frequent poly-adenosine stretches that alone necessitates unique adaptions of the translational machinery to prevent ribosome stalling or frameshifting [35,36]. Additionally, there are a limited number of ribosomal RNA copies within the genome, each with stage specific expression [37,38].…”

PfD123 modulates K13-mediated survival and recovery after artemisinin exposure

“…The immediate stress response (cluster 2, Fig. 2e top panel) includes Hsp70-1, which has been previously shown to be transcriptionally induced in response to amino acid starvation (Pavlovic Djuranovic et al, 2020) and to be induced by the ApiAP2 transcription factor PfAP2-HS (PF3D7_1342900) after heat shock (Tintó-Font et al, 2021), suggesting it may be a central early stress response gene in the Plasmodium ISR downstream of various stimuli. Several other chaperones as well as the drug efflux pump MDR1 were also induced.…”