The molecular machinery of translational control in malaria parasites

Abstract

Summary Translational control regulates the levels of protein synthesized from its transcript and is key for the rapid adjustment of gene expression in response to environmental stimuli. The regulation of translation is of special importance for malaria parasites, which pass through a complex life cycle that includes various replication phases in the different organs of the human and mosquito hosts and a sexual reproduction phase in the mosquito midgut. In particular, the quiescent transmission stages rely on translational control to rapidly adapt to the new environment, once they switch over from the human to the mosquito and vice versa. Three control mechanisms are currently proposed in Plasmodium, (1) global regulation that acts on the translation initiation complex; (2) mRNA‐specific regulation, involving cis control elements, mRNA‐binding proteins and translational repressors; and (3) induced mRNA decay by the Ccr4‐Not and the RNA exosome complex. The main molecules controlling translation are highly conserved in malaria parasites and an increasing number of studies shed light on the interwoven pathways leading to the up or downregulation of protein synthesis in the diverse plasmodial stages. We here highlight recent findings on translational control during life cycle progression of Plasmodium and discuss the molecules involved in regulating protein synthesis.

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

“…Phosphorylation of eIF2α results in repression of general protein translation and is a well-known mechanism of stress response, since mRNA encoding for proteins from stress response still translated. [29][30][31] Our studies lead us to conclude that synchronization upon melatonin requires not only the PfPK7 32 but also involves PfeIK1. Moreover, indol-related compounds are equally involved in the cell cycle progression, which explains synthetic indol-related compounds' ability to block parasite proliferation in PfeIK1 knockout parasite strain.…”

“…Phosphorylation of eIF2 occurs mainly in response to cell stress and results in an arrest in protein translation, 30 which could result in an arrest of cell cycle progression.…”

Preparing for Transmission: Gene Regulation in Plasmodium Sporozoites

“…Prediction of domain architecture has been used to improve domain recognition methods in Plasmodium genomes, expanding new predicted domains up to 30% in P. falciparum (platform Plasmobase) (Bernardes et al, 2017;Briquet et al, 2018). While many transcription or translation associated proteins have been predicted in Plasmodium through bioinformatics (Roos et al, 2001;Bischoff and Vaquero, 2010;Bennink and Pradel, 2019), only a few of them have been biologically investigated, and it is plausible that other yet unidentified proteins play key roles in the gene regulation networks that concur to the progression of Plasmodium through its developmental stages. In addition, the genome extreme AT richness in some species such as P. falciparum, with more than 80% AT especially in intergenic regions, is a major obstacle for the identification of cis-regulatory elements.…”

“…Translational regulation plays an important role in quiescent Plasmodium transmission stages, i.e., sporozoites and gametocytes, allowing rapid adjustment of gene expression and protein synthesis in response to the new environment that the parasite encounters when transiting from the mosquito vector to the mammalian host, and reciprocally (Bennink and Pradel, 2019). The eukaryote translation machinery is conserved in Plasmodium, where bioinformatics predict the presence of initiation, elongation and termination proteins (Cui et al, 2015;Bennink and Pradel, 2019). Many of the factors involved in translation regulation are expressed in sporozoites, as shown by mass spectrometry (Figure 2B and Table S2).…”

“…For details on protein identity and mass spectrometry results, see Table S1. (B) Number of post-transcriptional and translational regulators, based on the classification ofReddy et al (2015) andBennink and Pradel (2019). Black bars represent proteins with mass spectrometry evidence in Plasmodium spp.…”