Article abstract
Nature Chemical Biology 4, 203 - 213 (2008)
Published online: 3 February 2008 | doi:10.1038/nchembio.70
Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum
Shirin Arastu-Kapur1,
Elizabeth L Ponder2,
Ur
a Pe
ar Fonovi
1,
Sharon Yeoh3,
Fang Yuan1,6,
Marko Fonovi1,4,
Munira Grainger3,
Carolyn I Phillips2,
James C Powers5
&
Matthew Bogyo1
Abstract
Newly replicated Plasmodium falciparum parasites escape from host erythrocytes through a tightly regulated process that is mediated by multiple classes of proteolytic enzymes. However, the identification of specific proteases has been challenging. We describe here a forward chemical genetic screen using a highly focused library of more than 1,200 covalent serine and cysteine protease inhibitors to identify compounds that block host cell rupture by P. falciparum. Using hits from the library screen, we identified the subtilisin-family serine protease PfSU B1 and the cysteine protease dipeptidyl peptidase 3 (DPAP3) as primary regulators of this process. Inhibition of both DPAP3 and PfSUB1 caused a block in proteolytic processing of the serine repeat antigen (SERA) protein SERA5 that correlated with the observed block in rupture. Furthermore, DPAP3 inhibition reduced the levels of mature PfSUB1. These results suggest that two mechanistically distinct proteases function to regulate processing of downstream substrates required for efficient release of parasites from host red blood cells.
- Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
- Department of Microbiology and Immunology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
- Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
- Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
- Department of Chemistry, Georgia Institute of Technology, 901 Atlantic Drive, Atlanta, Georgia 30332, USA.
- Present address: EnzMed (Nanjing) Co., Ltd., 28 Hengjing Road, Nanjing, China 210046.
Correspondence to: Matthew Bogyo1 e-mail: mbogyo@stanford.edu
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