Malaria Parasite Signal Peptide Peptidase is an ER-Resident Protease Required for Growth but not for Invasion

Danushka S. Marapana, Danny W Wilson, Elizabeth S. Zuccala, Chaitali D. Dekiwadia, James G. Beeson, Stuart A Ralph, Jake Baum

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

Abstract

The establishment of parasite infection within the human erythrocyte is an essential stage in the development of malaria disease. As such, significant interest has focused on the mechanics that underpin invasion and on characterization of parasite molecules involved. Previous evidence has implicated a presenilin-like signal peptide peptidase (SPP) from the most virulent human malaria parasite, Plasmodium falciparum, in the process of invasion where it has been proposed to function in the cleavage of the erythrocyte cytoskeletal protein Band 3. The role of a traditionally endoplasmic reticulum (ER) protease in the process of red blood cell invasion is unexpected. Here, using a combination of molecular, cellular and chemical approaches we provide evidence that PfSPP is, instead, a bona fide ER-resident peptidase that remains intracellular throughout the invasion process. Furthermore, SPP-specific drug inhibition has no effect on erythrocyte invasion whilst having low micromolar potency against intra-erythrocytic development. Contrary to previous reports, these results show that PfSPP plays no role in erythrocyte invasion. Nonetheless, PfSPP clearly represents a potential chemotherapeutic target to block parasite growth, supporting ongoing efforts to develop antimalarial-targeting protein maturation and trafficking during intra-erythrocytic development.

Original languageEnglish
Pages (from-to)1457-1465
Number of pages9
JournalTraffic
Volume13
Issue number11
DOIs
Publication statusPublished - Nov 2012
Externally publishedYes

Keywords

  • Endoplasmic reticulum
  • Gamma-secretase
  • Malaria
  • Merozoite
  • Microneme
  • Plasmodium falciparum
  • Presenilin
  • Signal peptide peptidase
  • Tight junction

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