The malaria parasite Plasmodium falciparum Sortilin is essential for merozoite formation and apical complex biogenesis

Abstract

The inner membrane complex and the apical secretory organelles are defining features of apicomplexan parasites. Despite their critical roles, the mechanisms behind the biogenesis of these structures in the malaria parasite Plasmodium falciparum are still poorly defined. We here show that decreasing expression of the P. falciparum homologue of the conserved endolysomal escorter Sortilin-VPS10 prevents the formation of the inner membrane complex and abrogates the generation of new merozoites. Moreover, protein trafficking to the rhoptries, the micronemes, and the dense granules is disrupted, which leads to the accumulation of apical complex proteins in the endoplasmic reticulum and the parasitophorous vacuole. We further show that protein export to the erythrocyte and transport through the constitutive secretory pathway are functional. Taken together, our results suggest that the malaria parasite P. falciparum Sortilin has potentially broader functions than most of its other eukaryotic counterparts.

PfVPS45 Is Required for Host Cell Cytosol Uptake by Malaria Blood Stage Parasites

“…Our knock-sideways results indicate that VPS45 is needed for further maturation or fusion of these intermediates (or vesicles thereof) with the food vacuole. Hence, in contrast to the endolysosomal proteins previously functionally analyzed in apicomplexans that were found to have roles in secretion (Breinich et al, 2009;Dou et al, 2014;Hallee et al, 2018;Jimenez-Ruiz et al, 2016;Kremer et al, 2013;McGovern et al, 2018;Pieperhoff et al, 2013;Sangare et al, 2016;Tomavo et al, 2013), VPS45 is needed for endocytic trafficking.…”

“…However, it should be noted that the configuration of the endolysosomal system in malaria parasites may differ from that of other apicomplexans or that of well-characterized model organisms. The repurposing of endolysosomal factors for secretory trafficking via an endosome-like compartment nevertheless is conserved (Hallee et al, 2018;Krai et al, 2014). The identification of VPS45 as a protein functioning in endolysosomal transport therefore represents an entry point to unravel the proteins mediating HCCU and to differentiate endolysosomal factors in apicomplexan secretion from those involved in endocytosis.…”

“…Uptake of host cell material was also observed in the apicomplexan Toxoplasma gondii, indicating that it may be a commonplace process in apicomplexans, but again the underlying molecular mechanism is so far unclear (Dou et al, 2014;Jimenez-Ruiz et al, 2016;McGovern et al, 2018). Previous work indicated that apicomplexans repurposed parts of the endosomal system for the genesis of the secretory organelles required for host cell invasion (Breinich et al, 2009;Hallee et al, 2018;Jimenez-Ruiz et al, 2016;Krai et al, 2014;Kremer et al, 2013;McGovern et al, 2018;Pieperhoff et al, 2013;Sangare et al, 2016;Tomavo, 2014;Tomavo et al, 2013). For instance, in T. gondii, all three Rab5 paralogs are found in the late secretory pathway, and two play a role in the transport of secretory cargo (Kremer et al, 2013), giving no indication of a possible role in endocytosis.…”

Antimalarial Peptide and Polyketide Natural Products from the Fijian Marine Cyanobacterium Moorea producens

“…Since the malarial parasite life cycle requires entry into human erythrocytes, inhibiting the ability of Plasmodium to invade host cells could be a viable mechanism of action. The malarial protein with the next highest mTC and precision values for binding 1, sortilin, is important for the formation of apical complex components and creation of merozoites [34]. In parasite strains where the expression of sortilin is suppressed, new merozoites, which are the invasive form of the parasite, cannot be formed.…”

Who Needs a Contractile Actomyosin Ring? The Plethora of Alternative Ways to Divide a Protozoan Parasite

“…PfCINCH colocalizes with PfMORN1 at the basal complex, and interacts with the Plasmodium -specific proteins, basal complex protein 1 (PfBCP1) and basal complex transmembrane protein 2 (PfBTP2); PfBTP1 also colocalizes with PfMORN1 and may be involved in the interactions between the invaginating parasite plasma membrane and the inner membrane complex during the latter stages of cytokinesis (Kono et al, 2016). Finally, a trafficking protein, PfSortilin, is essential for inner membrane complex and basal complex contractile ring formation and the generation of merozoites, also playing a role in apicoplast segregation (Hallee et al, 2018), although its T. gondii ortholog is not required for pellicle formation (Sloves et al, 2012).…”