Understanding how African trypanosomes impair a subsequent Plasmodium infection

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A crucial role for the C‐terminal domain of exported protein 1 during the mosquito and hepatic stages of the Plasmodium bergheilife cycle

Publication . Wolanin, Kamil; Fontinha, Diana; Sanches-Vaz, Margarida; Nyboer, Britta; Heiss, Kirsten; Mueller, Ann‐Kristin; Prudêncio, Miguel

Intracellular Plasmodium parasites develop inside a parasitophorous vacuole (PV), a specialised compartment enclosed by a membrane (PVM) that contains proteins of both host and parasite origin. Although exported protein 1 (EXP1) is one of the earliest described parasitic PVM proteins, its function throughout the Plasmodium life cycle remains insufficiently understood. Here, we show that whereas the N-terminus of Plasmodium berghei EXP1 (PbEXP1) is essential for parasite survival in the blood, parasites lacking PbEXP1's entire C-terminal (CT) domain replicate normally in the blood but cause less severe pathology than their wild-type counterparts. Moreover, truncation of PbEXP1's CT domain not only impairs parasite development in the mosquito but also abrogates PbEXP1 localization to the PVM of intrahepatic parasites, severely limiting their replication and preventing their egress into the blood. Our findings highlight the importance of EXP1 during the Plasmodium life cycle and identify this protein as a promising target for antiplasmodial intervention.

2019Journal article

Open access

N6-methyladenosine in poly(A) tails stabilize VSG transcripts

Publication . Viegas, Idálio; Macedo, Juan; Serra, Lúcia; De Niz, Mariana; Temporão, Adriana; Silva Pereira, Sara; Mirza, Aashiq H.; Bergstrom, Ed; Rodrigues, Joao A.; Aresta Branco, Francisco; Jaffrey, Samie R.; Figueiredo, Luisa M.

RNA modifications are important regulators of gene expression1. In Trypanosoma brucei, transcription is polycistronic and thus most regulation happens post-transcriptionally2. N6-methyladenosine (m6A) has been detected in this parasite, but its function remains unknown3. Here we found that m6A is enriched in 342 transcripts using RNA immunoprecipitation, with an enrichment in transcripts encoding variant surface glycoproteins (VSGs). Approximately 50% of the m6A is located in the poly(A) tail of the actively expressed VSG transcripts. m6A residues are removed from the VSG poly(A) tail before deadenylation and mRNA degradation. Computational analysis revealed an association between m6A in the poly(A) tail and a 16-mer motif in the 3' untranslated region of VSG genes. Using genetic tools, we show that the 16-mer motif acts as a cis-acting motif that is required for inclusion of m6A in the poly(A) tail. Removal of this motif from the 3' untranslated region of VSG genes results in poly(A) tails lacking m6A, rapid deadenylation and mRNA degradation. To our knowledge, this is the first identification of an RNA modification in the poly(A) tail of any eukaryote, uncovering a post-transcriptional mechanism of gene regulation.

2022Journal article

Restricted access