Homing in on getting out : characterisation of SERA6, a putative malarial protease with a role in egress

• Main Author: Ruecker, A.
• Published: University College London (University of London) 2012
• Subjects: 616
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.565609

The human malaria parasite, P. falciparum, replicates within a membrane-bound intraerythrocytic parasitophorous vacuole (PV). The resulting daughter merozoites actively escape from the host cell in a process called egress. There is convincing evidence that proteases are key players in this step. These proteases could serve as excellent targets for the development of new antimalarial drugs. P. falciparum Serine Repeat Antigens (SERAs) form a family of 9 proteins all containing a central papain-like domain that identifies them as putative cysteine proteases. They are highly conserved throughout all Plasmodium species, and there is strong genetic evidence that they may play a role in egress. P. falciparum SERA6 is one of the most highly-expressed SERAs in asexual erythrocyte stages. In this study biochemical fractionation and indirect immunofluorescence analysis were used to confirm localisation of SERA6 to the PV. It was shown that SERA6 is a substrate for PfSUB1, a subtilisin-like protease which is crucial for egress and which is released into the PV just prior to egress. SERA6 is cleaved by PfSUB1 at 3 positions, releasing the papain-like domain. Processing of SERA6 by PfSUB1 is partially indispensable in in vitro P. falciparum parasites, as some mutations in SERA6 that block cleavage are not tolerated in the parasite. In addition, the putative catalytic Cys of SERA6 cannot be replaced with a non-catalytic Ala residue in the parasite, indicating SERA6 is an indispensable cysteine protease. Finally it was demonstrated that PfSUB1-mediated processing of the P. berghei orthologue of SERA6 converts it to an active cysteine protease. It can be proposed that SERA6 is a key player in a proteolytic cascade that leads to egress of the blood-stage malaria parasite.