Abstract
Trypanosoma cruzi, the etiological agent of Chagas' disease, is an early divergent eukaryote in which control of gene expression relies mainly in post-transcriptional mechanisms. Transcription levels are globally up and down regulated during the transition between proliferating and non-proliferating life-cycle stages. In this work we characterized a nuclear adenylate kinase isoform (TcADKn) that is involved in ribosome biogenesis. Nuclear adenylate kinases have been recently described in a few organisms, being all related to RNA metabolism. Depending on active transcription and translation, TcADKn localizes in the nucleolus or the cytoplasm. A non-canonical nuclear localization signal was mapped towards the N-terminal of the protein, being the phosphate-binding loop essential for its localization. In addition, TcADKn nuclear exportation depends on the nuclear exportation adapter CRM1. TcADKn nuclear shuttling is governed by nutrient availability, oxidative stress and by the equivalent in T. cruzi of the mammalian TOR (Target of Rapamycin) pathway. One of the biological functions of TcADKn is ribosomal 18S RNA processing by direct interaction with ribosomal protein TcRps14. Finally, TcADKn expression is regulated by its 3′ UTR mRNA. Depending on extracellular conditions, cells modulate protein translation rates regulating ribosome biogenesis and nuclear adenylate kinases are probably key components in these processes.
Highlights
Trypanosoma cruzi, the causative agent of Chagas’ disease, is a protozoan parasite with a complex life cycle which involves two intermediary hosts, triatomine insects and mammals and three main parasite stages, epimastigotes and amastigotes which replicate in the insect vector and mammalian host respectively; and trypomastigotes the non-replicative form [1]
Sequence analysis revealed that they did not present canonical nuclear localization signals (NLS); TcADKn presented a leucine-rich region towards the C-terminal of the protein, similar to the typical nuclear exportation signals (NES) that are recognized by the CRM1 transporter (Chromosome Region Maintenance 1 protein, or Exportin-1) [41]
TcADKn amino acid sequence is highly divergent from the other six isoforms of ADKs previously characterized in T. cruzi, which is clearly reflected in the low similarity and identity percentages between each other (Figure S1B, Table S1)[30]
Summary
Trypanosoma cruzi, the causative agent of Chagas’ disease, is a protozoan parasite with a complex life cycle which involves two intermediary hosts, triatomine insects and mammals and three main parasite stages, epimastigotes and amastigotes which replicate in the insect vector and mammalian host respectively; and trypomastigotes the non-replicative form [1]. The complexity of its life cycle involves multiple morphological and metabolic changes that are possible due to a strict control of gene expression [2]. Trypanosomatids present unique characteristics regarding ribosome structure [11,12] and ribosomal locus organization [13]. There is almost no information about ribosome biogenesis in trypanosomatids, but their extremely divergent ribosomal locus suggests that they might present unique characteristics in ribosome biogenesis and assembly. For example in T. brucei ribosomal 5S rRNA biogenesis involves proteins which are exclusively found in trypanosomatids [14,15,16]
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