Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: A potential strategy to interfere with parasite virulence

Abstract

Background: Reversible modification of proteins through the attachment of ubiquitin or ubiquitin-like modifiers is an essential post-transnational regulatory mechanism in eukaryotes, The conjugation of ubiquitin or ubiquitin-like proteins has been demonstrated to play roles in growth, adaptation and homoestasis in all eukaryotes, with perturbation of ubiquitin-mediated systems associated with pathogenesis of many human diseases, including cancer and neurodegenerative disorders. Methodology/principal Findings: Here 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 comnplexity. 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. Conlusion/Significance: This study provides a comprehensive analysis of proteins predicted to be involved in the apicomplexan ubiquitin-mediated pathway. Given the importance of such pathay 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. © 2008 Ponts et al.