Journal
NATURE MICROBIOLOGY
Volume 3, Issue 4, Pages 447-455Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41564-018-0111-0
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Funding
- Francis Crick Institute - Cancer Research UK [FC001043]
- UK Medical Research Council [FC001043]
- Wellcome Trust [FC001043]
- Crick PhD studentships
- Gatan BBSRC CASE PhD studentship [BB/F016948/1]
- MRC [G1100013, MR/P010288/1]
- Wellcome equipment grants [101488, 079605, 086018]
- Wellcome ISSF2
- BBSRC [BB/F016948/1] Funding Source: UKRI
- MRC [G1100013, MR/P010288/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1104845] Funding Source: researchfish
- Medical Research Council [1365576, G1100013, MR/P010288/1] Funding Source: researchfish
- The Francis Crick Institute [10043, 10400, 10011, 106239/Z/14/A] Funding Source: researchfish
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Malaria parasites replicate within a parasitophorous vacuole in red blood cells (RBCs). Progeny merozoites egress upon rupture of first the parasitophorous vacuole membrane (PVM), then poration and rupture of the RBC membrane (RBCM). Egress is protease-dependent(1), but none of the effector molecules that mediate membrane rupture have been identified and it is unknown how sequential rupture of the two membranes is controlled. Minutes before egress, the parasite serine protease SUB1 is discharged into the parasitophorous vacuole(2-6) where it cleaves multiple substrates(2,5,7-9) including SERA6, a putative cysteine protease(10-12). Here, we show that Plasmodium falciparum parasites lacking SUB1 undergo none of the morphological transformations that precede egress and fail to rupture the PVM. In contrast, PVM rupture and RBCM poration occur normally in SERA6-null parasites but RBCM rupture does not occur. Complementation studies show that SERA6 is an enzyme that requires processing by SUB1 to function. RBCM rupture is associated with SERA6-dependent proteolytic cleavage within the actin-binding domain of the major RBC cytoskeletal protein beta-spectrin. We conclude that SUB1 and SERA6 play distinct, essential roles in a coordinated proteolytic cascade that enables sequential rupture of the two bounding membranes and culminates in RBCM disruption through rapid, precise, SERA6-mediated disassembly of the RBC cytoskeleton.
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