Nedd8 hydrolysis by UCH proteases in Plasmodium parasites

English version

Autoři: Maryia Karpiyevich ^aff001; Sophie Adjalley ^aff002; Marco Mol ^aff001; David B. Ascher ^aff003; Bethany Mason ^aff001; Gerbrand J. van der Heden van Noort ^aff005; Heike Laman ^aff001; Huib Ovaa ^aff005; Marcus C. S. Lee ^aff002; Katerina Artavanis-Tsakonas ^aff001
Působiště autorů: Department of Pathology, University of Cambridge, Cambridge, United Kingdom ^aff001; Parasites and Microbes Programme, Wellcome Sanger Institute, Cambridge, United Kingdom ^aff002; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom ^aff003; Department of Biochemistry, University of Melbourne, Melbourne, Australia ^aff004; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands ^aff005
Vyšlo v časopise: Nedd8 hydrolysis by UCH proteases in Plasmodium parasites. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1008086
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008086

Souhrn

Plasmodium parasites are the causative agents of malaria, a disease with wide public health repercussions. Increasing drug resistance and the absence of a vaccine make finding new chemotherapeutic strategies imperative. Components of the ubiquitin and ubiquitin-like pathways have garnered increased attention as novel targets given their necessity to parasite survival. Understanding how these pathways are regulated in Plasmodium and identifying differences to the host is paramount to selectively interfering with parasites. Here, we focus on Nedd8 modification in Plasmodium falciparum, given its central role to cell division and DNA repair, processes critical to Plasmodium parasites given their unusual cell cycle and requirement for refined repair mechanisms. By applying a functional chemical approach, we show that deNeddylation is controlled by a different set of enzymes in the parasite versus the human host. We elucidate the molecular determinants of the unusual dual ubiquitin/Nedd8 recognition by the essential PfUCH37 enzyme and, through parasite transgenics and drug assays, determine that only its ubiquitin activity is critical to parasite survival. Our experiments reveal interesting evolutionary differences in how neddylation is controlled in higher versus lower eukaryotes, and highlight the Nedd8 pathway as worthy of further exploration for therapeutic targeting in antimalarial drug design.

Klíčová slova:

Crystal structure – Enzymes – Hydrolysis – Malarial parasites – Parasitic diseases – Plasmodium – Plasmodium falciparum – Proteasomes

Zdroje

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