Ectopic overexpression of <i>Plasmodium falciparum</i> DNA-/RNA-binding Alba proteins misregulates virulence gene homeostasis during asexual blood development
Notice bibliographique
Résumé
ABSTRACT Alba domain-containing proteins are ubiquitously found in archaea and eukaryotes. By binding to either DNA, RNA, or DNA:RNA hybrids, these proteins function in genome stabilization, chromatin organization, gene regulation, and/or translational modulation. In the malaria parasite Plasmodium falciparum , six Alba domain proteins PfAlba1–6 have been described, of which PfAlba1 has emerged as a “master regulator” of translation during parasite intra-erythrocytic development (IED). Given that a tight control of gene expression is especially important during IED, when malaria pathogenesis manifests, in this study, we focus on three other P. falciparum Albas, PfAlba2–4. Because genetic manipulation of the genomic loci of PfAlba2–4 was unsuccessful, we overexpressed each of these proteins from an episome under a strong constitutive promoter. We observed that PfAlba2 or PfAlba3 overexpression strongly reduced parasite growth and impacted IED stage transitions. In contrast, elevated levels of PfAlba4 were well-tolerated by the parasite. In keeping with this, differential gene expression analysis using RNA-seq of PfAlba2 or PfAlba3 overexpressing strains revealed a significant misregulation of mRNAs encoding virulence factors, such as those related to erythrocyte invasion; a general repression of var gene expression was also apparent. PfAlba4 overexpression, on the other hand, did not significantly perturb the steady-state transcriptome of IED stages and appeared to enhance var mRNA levels. Moreover, distinct sets of genes were targeted by each PfAlba for regulation. Taken together, this study highlights the nonredundant roles of PfAlba proteins in the P. falciparum IED, emphasizing their importance in subtelomeric chromatin biology and RNA regulation. IMPORTANCE The malaria parasite Plasmodium falciparum tightly controls the expression of its genes at the epigenetic, transcriptional, post-transcriptional, and translational levels to synthesize essential proteins, including virulence factors, in a timely and spatially coordinated manner. A family of six proteins implicated in this process is called PfAlba, characterized by the presence of the DNA-, RNA- or DNA:RNA hybrid-binding Alba domain. To better understand the cellular pathways regulated by this protein family, we overexpressed three PfAlbas during P. falciparum intra-erythrocytic growth and found that high levels of PfAlba2 and PfAlba3 were detrimental to parasite development. This was accompanied by significant changes in the parasite’s transcriptome, either with regards to mRNA steady-state levels or expression timing. PfAlba4 overexpression, on the other hand, was well-tolerated by the parasite. Overall, our results delineate specific pathways targeted by individual PfAlbas for regulation and link PfAlba2/PfAlba3 to mutually exclusive expression of the virulence-promoting surface antigen PfEMP1.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».