Abstract
The flagellar pocket constitutes an active and strategic site in the body of trypanosomatids (i.e. parasitic protozoa that cause important human and/or livestock diseases), which participates in several important processes such as cell polarity, morphogenesis and replication. Most importantly, the flagellar pocket is the unique site of surface protein export and nutrient uptake in trypanosomatids, and thus constitutes a key portal for the interaction with the host. In this work, we identified and characterized a novel Trypanosoma cruzi protein, termed TCLP 1, that accumulates at the flagellar pocket area of parasite replicative forms, as revealed by biochemical, immuno-cytochemistry and electron microscopy techniques. Different in silico analyses revealed that TCLP 1 is the founding member of a family of chimeric molecules restricted to trypanosomatids bearing, in addition to eukaryotic ubiquitin-like and protein-protein interacting domains, a motif displaying significant structural homology to bacterial multi-cargo chaperones involved in the secretion of virulence factors. Using the fidelity of an homologous expression system we confirmed TCLP 1 sub-cellular distribution and showed that TCLP 1-over-expressing parasites display impaired survival and accelerated progression to late stationary phase under starvation conditions. The reduced endocytic capacity of TCLP 1-over-expressors likely underlies (at least in part) this growth phenotype. TCLP 1 is involved in the uptake of extracellular macromolecules required for nutrition and hence in T. cruzi growth. Due to the bacterial origin, sub-cellular distribution and putative function(s), we propose TCLP 1 and related orthologs in trypanosomatids as appealing therapeutic targets for intervention against these health-threatening parasites.
Highlights
Trypanosoma cruzi is the causative of Chagas Disease, a major health and economic issue in Latin America for which no vaccine or appropriate drugs for large-scale public-healthPLOS ONE | DOI:10.1371/journal.pone.0130099 June 18, 2015A CesT-Like Protein in Trypanosoma cruzi
This molecule, termed TCLP 1::3xFLAG (TCLP 1) (Trypanosomatid CesT-like Protein 1), is conserved among trypanosomatids, and bears 3 homology inferred domains: an N-terminal Ubiquitin-Like Domain (UBL) [15], a C-terminal PSD95/Dlg1/zo-1 (PDZ) domain, which is involved in protein-protein interaction phenomena [16], and a domain with structural homology to CesT (Chaperone for E. coli secretion of Tir), which is a multi-cargo chaperone conserved in enteropathogenic bacteria that contributes to the secretion of virulence factors through type III secretion systems (TIIISS) [17, 18]
TCLP 1 emerged as a top-ranked candidate during an in silico screening aimed at identifying proteins potentially involved in modulating host cellular processes during a T. cruzi infection
Summary
After a series of division rounds within the cytoplasm of infected cells, amastigotes differentiate into trypomastigotes (with evident flagella and undulating membrane), which represent the infective, non-replicative mammalian form [2] As part of their evolutionary adaptation, trypanosomatids have developed highly specialized cellular organelles and anatomical structures [3]. We identified a novel T. cruzi molecule which accumulates in the FP area of replicative forms (i.e. epimastigotes and amastigotes) This molecule, termed TCLP 1 (Trypanosomatid CesT-like Protein 1), is conserved among trypanosomatids, and bears 3 homology inferred domains: an N-terminal Ubiquitin-Like Domain (UBL) [15], a C-terminal PSD95/Dlg1/zo-1 (PDZ) domain, which is involved in protein-protein interaction phenomena [16], and a domain with structural homology to CesT (Chaperone for E. coli secretion of Tir), which is a multi-cargo chaperone conserved in enteropathogenic bacteria that contributes to the secretion of virulence factors through type III secretion systems (TIIISS) [17, 18].
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