Ubiquitin Proteasome pathway proteins as potential drug targets in parasite Trypanosoma cruzi

Abstract

Trypanosomiasis infects more than 21 million people and claims approximately 2 million lives annually. Due to the development of resistance against currently available anti-trypanosomal drugs, there is a growing need for specific inhibitors and novel drug targets. Of late, the proteins from the Ubiquitin Proteasome Pathway (UPP): ubiquitin ligases and deubiquitinase have received attention as potential drug targets in other parasites from the apicomplexan family. The completion of Trypanosoma cruzi (Tc) genome sequencing in 2005 and subsequent availability of database resources like TriTrypDB has provided a platform for the systematic study of the proteome of this parasite. Here, we present the first comprehensive survey of the UPP enzymes, their homologs and other associated proteins in trypanosomes and the UPPs from T. cruzi were explored in detail. After extensive computational analyses using various bioinformatics tools, we have identified 269 putative UPP proteins in the T. cruzi proteome along with their homologs in other Trypanosoma species. Characterization of T. cruzi proteome was done based on their predicted subcellular localization, domain architecture and overall expression profiles. Specifically, unique domain architectures of the enzymes and the UPP players expressed exclusively in the amastigote stage provide a rationale for designing inhibitors against parasite UPP proteins.

Transcriptome-Wide Comparisons and Virulence Gene Polymorphisms of Host-Associated Genotypes of the Cnidarian Parasite Ceratonova shasta in Salmonids

“…In trypanosomes, protein degradation during parasite cell differentiation is primarily proteasome dependent, and proteasome inhibition impedes differentiation and transformation from noninfectious epimastigotes to infective tryptomastigotes ( Cardoso et al. 2011 ; Gupta et al. 2018 ).…”

Molecular Characterization of Tc964, A Novel Antigenic Protein from Trypanosoma cruzi

“…Consisting with its potential GTPase activity, the Western blot assays revealed a signal of higher molecular weight (45 kDa) which could correspond to a post-translational modification due to the binding of a ubiquitin molecule. In GTPases, ubiquitination is a common post-translational modification that allows these proteins to fulfill their function of maintaining the GTP cycle [53] and modulates the location of proteins as well as protein-protein interactions having direct effects on expression levels [54,55]. The study of the Tc964 interactome strengthens the hypothesis of a possible in vivo interaction of Tc964 with a protein from the T. cruzi ubiquitin family [56].…”

Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

“…In T. brucei , T. cruzi and Leishmania, ubiquitination has not yet been extensively investigated, but it is clear from genome-wide RNAi screens, genome analysis, and reports on specific cellular processes that also in these parasites this modification plays an essential and widespread role. Genome-wide analysis shows that genes encoding for orthologues of ubiquitin E1, E2 and E3 proteins are all present in these species, as are enzymes involved in de-ubiquitination ( Gupta et al, 2018 ). Ubiquitin E1 proteins can be identified by the presence of two ThiF/MoeB motifs and a C-terminal ubiquitin fold domain (UFD) ( Schulman and Harper, 2009 ).…”