Proto, W. R., Castanys-Munoz, E., Black, A., Tetley, L., Moss, C. X., Juliano, L., Coombs, G. H. and Mottram, J. C. (2011) Trypanosoma brucei metacaspase 4 is a pseudopeptidase and a virulence factor. Journal of Biological Chemistry, 286(46), pp. 39914-39925. (doi: 10.1074/jbc.M111.292334)
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Publisher's URL: http://dx.doi.org/10.1074/jbc.M111.292334
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 (Delta mca4) was possible. Delta 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.
| Item Type: | Articles |
|---|---|
| Additional Information: | Author's Choice option |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Castanys-Munoz, Dr Esther and Coombs, Professor Graham and Tetley, Dr Laurence and Mottram, Professor Jeremy |
| Authors: | Proto, W. R., Castanys-Munoz, E., Black, A., Tetley, L., Moss, C. X., Juliano, L., Coombs, G. H., and Mottram, J. C. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Life Sciences |
| Journal Name: | Journal of Biological Chemistry |
| Journal Abbr.: | J Biol Chem. |
| Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
| ISSN: | 0021-9258 |
| ISSN (Online): | 1083-351X |
| Published Online: | 23 September 2011 |
| Copyright Holders: | Copyright © 2011 American Society for Biochemistry and Molecular Biology |
| First Published: | First published in Journal of Biological Chemistry 286(46):39914-39925 |
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