Deciphering the Ubiquitin-Mediated Pathway in Apicomplexan Parasites: A Potential Strategy to Interfere with Parasite Virulence

Abstract

BackgroundReversible modification of proteins through the attachment of ubiquitin or ubiquitin-like modifiers is an essential post-translational regulatory mechanism in eukaryotes. The conjugation of ubiquitin or ubiquitin-like proteins has been demonstrated to play roles in growth, adaptation and homeostasis in all eukaryotes, with perturbation of ubiquitin-mediated systems associated with the pathogenesis of many human diseases, including cancer and neurodegenerative disorders.Methodology/Principal FindingsHere we describe the use of an HMM search of functional Pfam domains found in the key components of the ubiquitin-mediated pathway necessary to activate and reversibly modify target proteins in eight apicomplexan parasitic protozoa for which complete or late-stage genome projects exist. In parallel, the same search was conducted on five model organisms, single-celled and metazoans, to generate data to validate both the search parameters employed and aid paralog classification in Apicomplexa. For each of the 13 species investigated, a set of proteins predicted to be involved in the ubiquitylation pathway has been identified and demonstrates increasing component members of the ubiquitylation pathway correlating with organism and genome complexity. Sequence homology and domain architecture analyses facilitated prediction of apicomplexan-specific protein function, particularly those involved in regulating cell division during these parasite's complex life cycles.Conclusions/SignificanceThis study provides a comprehensive analysis of proteins predicted to be involved in the apicomplexan ubiquitin-mediated pathway. Given the importance of such pathway in a wide variety of cellular processes, our data is a key step in elucidating the biological networks that, in part, direct the pathogenicity of these parasites resulting in a massive impact on global health. Moreover, apicomplexan-specific adaptations of the ubiquitylation pathway may represent new therapeutic targets for much needed drugs against apicomplexan parasites.

Unraveling the Ubiquitome of the Human Malaria Parasite

“…The 60 S ribosomal protein L27a (PFF0885w) was found to be ubiquitylated at ring stage exclusively (5 spectral counts), and seven ubiquitin conjugates were trophozoite-specific (Table 3). Two of them are members of the ubiquitin/proteasome system in P. falciparum (10). UFD2 (PFD0265w) is a U-box ubiquitin ligase involved in the endoplasmic reticulum-associated protein degradation pathway Ubiquitylation in P. falciparum NOVEMBER 18, 2011 • VOLUME 286 • NUMBER 46…”

“…In P. falciparum, previous in silico studies identified four predicted sources of ubiquitin moieties. The polyubiquitin gene PFL0585w contains five conserved ubiquitin repeats (9,10). The two ubiquitin fusion proteins PfUB S27a and PfUB L40 (PF14_0027 and PF13_0346, respectively) contain a ubiquitin moiety at their N-terminal side (10).…”

“…The polyubiquitin gene PFL0585w contains five conserved ubiquitin repeats (9,10). The two ubiquitin fusion proteins PfUB S27a and PfUB L40 (PF14_0027 and PF13_0346, respectively) contain a ubiquitin moiety at their N-terminal side (10). More recently, one conserved ubiquitin domain was identified in PF08_0067 and is believed to be part of an endoplasmic reticulum-associated protein degradation (ERAD) 3 -like pathway (11).…”

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

“…HECT (homologous to the E6-AP carboxyl terminus) ubiquitin ligase E3] (Dataset S1), another gene in the ubiquitin-mediated pathway (34). Given the role of this pathway in directing protein degradation and recycling, it is possible that alterations in these genes create changes in stress responses or protein turnover of key resistance modulators that allow the parasite to survive under drug pressure.…”

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

“…In comparison, histone H4 sumoylation is associated with decreased gene expression (136). The malaria parasite genomes contain a number of protein homologues of E1, E2, and E3 and a number of proteases that might be involved in removing the Ubl modifications (118,120). In an effort to identify the proteome of PfSUMO modified proteins, Issar et al (74) identified sumoylated histone H4 from P. falciparum.…”