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Open Access research with a European policy impact...

The Strathprints institutional repository is a digital archive of University of Strathclyde's Open Access research outputs. Strathprints provides access to thousands of Open Access research papers by Strathclyde researchers, including by researchers from the European Policies Research Centre (EPRC).

EPRC is a leading institute in Europe for comparative research on public policy, with a particular focus on regional development policies. Spanning 30 European countries, EPRC research programmes have a strong emphasis on applied research and knowledge exchange, including the provision of policy advice to EU institutions and national and sub-national government authorities throughout Europe.

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Trypanosoma brucei metacaspase 4 is a pseudopeptidase and a virulence factor

Proto, William R and Castanys-Munoz, Esther and Black, Alana and Tetley, Laurence and Moss, Catherine X and Juliano, Luiz and Coombs, Graham H and Mottram, Jeremy C (2011) Trypanosoma brucei metacaspase 4 is a pseudopeptidase and a virulence factor. Journal of Biological Chemistry. ISSN 1083-351X

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Abstract

Metacaspases are caspase family cysteine peptidases found in plants, fungi and protozoa, but not mammals. Trypanosoma brucei is unusual in having five metacaspases (MCA1-MCA5) of which MCA1 and MCA4 have active site substitutions, making them possible non-enzymatic homologues. Here we demonstrate that recombinant MCA4 lacks detectable peptidase activity, despite maintaining a functional peptidase structure. MCA4 is expressed primarily in the bloodstream form of the parasite and associates with the flagellar membrane via dual myristoylation/palmitoylation. Loss of function phenotyping revealed critical roles for MCA4; rapid depletion by RNAi caused lethal disruption to the parasite's cell cycle, yet the generation of MCA4 null mutant parasites (mca4) was possible. mca4 had normal growth in axenic culture, but markedly reduced virulence in mice. Further analysis revealed that MCA4 is released from the parasite and is specifically processed by MCA3, the only metacaspase that is both palmitoylated and enzymatically active. Accordingly we have identified that the multiple metacaspases in T. brucei form a membrane-associated proteolytic cascade to generate a pseudopeptidase virulence factor.