The roles of intramembrane proteases in protozoan parasites

Abstract

Intramembrane proteolysis is widely conserved throughout different forms of life, with three major types of proteases being known for their ability to cleave peptide bonds directly within the transmembrane domains of their substrates. Although intramembrane proteases have been extensively studied in humans and model organisms, they have only more recently been investigated in protozoan parasites, where they turn out to play important and sometimes unexpected roles. Signal peptide peptidases are involved in endoplasmic reticulum (ER) quality control and signal peptide degradation from exported proteins. Recent studies suggest that repurposing inhibitors developed for blocking presenilins may be useful for inhibiting the growth of Plasmodium, and possibly other protozoan parasites, by blocking signal peptide peptidases. Rhomboid proteases, originally described in the fly, are also widespread in parasites, and are especially expanded in apicomplexans. Their study in parasites has revealed novel roles that expand our understanding of how these proteases function. Within this diverse group of parasites, rhomboid proteases contribute to processing of adhesins involved in attachment, invasion, intracellular replication, phagocytosis, and immune evasion, placing them at the vertex of host-parasite interactions. This article is part of a Special Issue entitled: Intramembrane Proteases.

Keywords: Adhesion; Apicomplexan parasite; Cell invasion; Rhomboid; Secretory pathway; Signal peptide peptidase.

Fig. 1

Analysis of conserved rhomboid proteases in Apicomplexan parasites. A) Phylogenetic tree of rhomboid proteases in apicomplexans compared to fly, human bacterial, and plant. Dm, Drosophila melanogaster, Hs, Homo sapiens, Mm, Mus musculus, Tg, Toxoplasma gondii, A. thaliana, Arabidopsis thaliana, O. sativa, Oryza sativa, P. syringae, Pseudomonas syringae, P. stuartii, Providencia stuartii, R. sphaerodies, Rhodobacter sphaerodies, P. falciparum, Plasmodium falciparum, P. yoellii, Plasmodium yoellii (GenBank accession numbers beneath each entry). Used with permission [1]. B) Cellular localization of rhomboid proteases in T. gondii tachyzoite. Image courtesy of Wandy Beatty.

Fig. 2

Role of TgROM4 in shedding of surface adhesins. A) In wild type parasites, shedding of surface adhesins maintains an anterior to posterior gradient that is critical for directional gliding and cell invasion. B) When TgROM is suppressed, adhesins accumulate on the cell surface, resulting in enhanced twirling in place, lack of polarized cell attachment and disruption of invasion. Used with permission [2].