Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis.

Abstract

Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of P.falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle.

• Authors: Michael Baldwin, Crystal Russo, Xuerong Li, Athar H Chishti
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 450 Issue 4 Pg. 1427-32 (Aug 08 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 25017910 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Heat-Shock Proteins
• Aspartic Acid Endopeptidases
• signal peptide peptidase

Topics

• Amino Acid Sequence
• Animals
• Aspartic Acid Endopeptidases (chemistry, metabolism)
• Germ Cells (cytology)
• Heat-Shock Proteins (metabolism)
• Microscopy, Fluorescence
• Molecular Sequence Data
• Plasmodium falciparum (enzymology)
• Proteolysis