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Dandewad, V. and Vindu, A. and Joseph, J. and Seshadri, V. (2019) Import of human miRNA-RISC complex into Plasmodium falciparum and regulation of the parasite gene expression. Journal of Biosciences, 44 (2).

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During its life cycle, the malarial parasite Plasmodium goes through different asexual stages in human blood, and asexual and sexual stage in mosquito. Expression of stage-specific proteins is important for successful completion of its life cycle and requires tight gene regulation. In case of Plasmodium, due to relative paucity of the transcription factors, it is postulated that post-transcriptional regulation plays an important role in stage-specific gene expression. Although miRNA-mediated gene regulation has been well-established to function in post-transcriptional regulation in many eukaryotes, existence of such a phenomenon or the presence of miRNA-associated factors in Plasmodium remains unclear. A number of miRNAs are shown to be imported into Plasmodium falciparum from erythrocytes and role of these miRNAs is not understood. Here we show that human Argonaute 2 (hAgo2) a component of the miRISC complex is imported by P. falciparum. In the parasite hAgo2 exists as in a complex with specific human miRNAs like let-7a and miR15a which can potentially target the Plasmodium genes Rad54 and Lipid/sterol:H+ symporter respectively. We show that hAgo2 associates with Rad54, Lipid/sterol:H+ symporter and other P. falciparum transcripts. These results highlight the existence of a mechanism by which malarial parasite imports hAgo2-miRNA complex from the host cells to regulate its gene expression. Malaria is one of the deadly infectious diseases, which is caused by parasitic protozoa of the genus Plasmodium. Members of Plasmodium genus cause different types of malaria in various organisms. In humans, malaria is caused by four species of Plasmodium, namely, P. falciparum, P. ovale, P. malariae and P. vivax. Malaria is transmitted by female Anopheles mosquito. In its complex life cycle, Plasmodium parasites undergo different infective, propagative, sexual and asexual stages, which are precisely timed in vertebrate and mosquito hosts. In order survive in these varied host environments and to successfully complete its life cycle, the parasite requires to achieve tightly controlled temporal regulation of gene expression (Kooij and Matuschewski 2007). P. falciparum genome has a relative paucity of transcriptional factors as compared to other eukaryotes (Coulson et al. 2004). It has been suggested that both post-transcriptional and post-translational gene regulation play an important role in development of P. falciparum in erythrocytes (Foth et al. 2008). Comparative gene expression profiling of different stages of P. berghei has indicated that there is no direct correlation between the abundance of mRNAs encoding specific proteins in a given stage and the abundance of the encoded proteins in that stage (Hall et al. 2005). Interestingly, there is a positive correlation between the abundance of mRNAs encoding specific proteins in a given stage and the abundance of the encoded proteins in the succeeding stage (Hall et al. 2005). This indicates that that the mRNA encoding the proteins required in a specific stage is synthesized in a previous stage, in a manner similar to what is observed for maternally expressed RNA during oocyte development. It is estimated that ~30% of human protein coding genes are regulated by miRNAs at the post-transcriptional level (Filipowicz et al. 2008). The miRNA binding sites are present mostly in the 3′-untranslated region (UTR) of the target mRNA, whereas miRNAs could also bind to the 5′UTR and the coding regions albeit to a lesser extent (Didiano and Hobert 2008; Zhou et al. 2009). Apart from their function in translational control, miRNAs also regulate gene expression at the transcriptional level by modulating the hypermethylation of target genes (Khraiwesh et al. 2010). Genomic studies have revealed that Plasmodium species lack the miRNA pathway (Baum et al. 2009). Because Plasmodium falciparum genome is highly AT rich, it is possible that bioinformatics analysis would have been unable to identify the miRNA pathway members due to the significant divergence of sequences (Dechering et al. 1998). Recently, it was shown that specific non-coding RNAs might act as precursor miRNAs to generate functional miRNA (Chakrabarti et al. 2007; Saraiya and Wang 2008). The Plasmodium snoRNAs (snoR15, snoR21 and snoR27), RNA of Unknown Function (RUF1, RUF2, RUF3, RUF4, RUF5 and RUF6) and spliceosomal RNAs (U1snRNAs, U2snRNAs, U4snRNAs, U5snRNAs) form similar stem and loop structure as do precursor miRNA from different organism. Furthermore, it was reported that erythrocytes have ~200 microRNAs despite lacking nucleus, mRNA, and the translation machinery (Chen et al. 2008; Kannan and Atreya 2010). It was also shown that erythrocytes have the miRNA complexed to Ago2 (Azzouzi et al. 2015). It has been found that higher level of specific miRNA in the host erythrocytes under sickle cell anemia condition reduces the infection by Plasmodium falciparum (Lamonte et al. 2012). It was shown that miR451, was covalently ligated to the P. falciparum mRNA at 5′end and impairs its translation. However, the mechanistic details of the ligation process and how the miRNA acts on its targets in P. falciparum are still unclear. The role of miRNAs in RBCs functions is not well-understood. It is possible that some of these miRNAs that have sequence complementarity to mRNAs from Plasmodium may regulate the gene expression in Plasmodium through an unknown mechanism. It has been shown that extracellular vesicles derived from infected RBC contain the components of the RISC complex (Mantel et al. 2013, 2016; Ofir-Birin et al. 2017; Regev-Rudzki et al. 2013). It was also shown recently that Plasmodium falciparum take up microparticle from RBC containing Ago2 and miRNA (Wang et al. 2017). We hypothesized that along with the miRNAs, components of miRISC are also imported into the parasite as functional miRNP complex. We envisaged that such a complex may be functional in regulating gene expression in Plasmodium. Here we show that specific miRNAs present in RBCs are taken up by the parasite, which could potentially target mRNAs from Plasmodium falciparum. We find that human RBCs not only contain hAgo2, but is also imported into Plasmodium falciparum. The imported hAgo2 is localized to specific regions within the parasite cell. We further show that the human hAgo2 exists in complex with miRNA from RBCs and the target mRNAs from the parasite. Collectively, these data suggest that Plasmodium imports the functional components of RBCs miRISC complex, which can regulate the gene expression in the parasite.

Item Type: Article
Depositing User: Mr. Rameshwar Nema
Date Deposited: 21 Feb 2020 04:05
Last Modified: 10 Feb 2021 07:41
URI: http://nccs.sciencecentral.in/id/eprint/723

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