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There, SUB1 activates a PV\u2010resident cysteine protease called SERA6, enabling host RBC rupture through SERA6\u2010mediated degradation of the RBC cytoskeleton protein \u03b2\u2010spectrin. Here, we show that the activation of\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    SERA6 involves a second, autocatalytic step that is triggered by SUB1 cleavage. Unexpectedly, autoproteolytic maturation of SERA6 requires interaction in multimolecular complexes with a distinct PV\u2010located protein cofactor, MSA180, that is itself a SUB1 substrate. Genetic ablation of MSA180 mimics SERA6 disruption, producing a fatal block in \u03b2\u2010spectrin cleavage and RBC rupture. Drug\u2010like inhibitors of SERA6 autoprocessing similarly prevent \u03b2\u2010spectrin cleavage and egress in both\n                    <jats:italic>P.\u00a0falciparum<\/jats:italic>\n                    and the emerging zoonotic pathogen\n                    <jats:italic>P.\u00a0knowlesi<\/jats:italic>\n                    . Our results elucidate the egress pathway and identify SERA6 as a target for a new class of antimalarial drugs designed to prevent disease progression.\n                  <\/jats:p>","DOI":"10.15252\/embj.2020107226","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T08:02:47Z","timestamp":1619856167000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3747-2365","authenticated-orcid":false,"given":"Michele S Y","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Koussis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrislaine","family":"Withers\u2010Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A","family":"Howell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1991-1838","authenticated-orcid":false,"given":"James A","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Hackett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Knuepfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambrosius P","family":"Snijders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7442-3810","authenticated-orcid":false,"given":"Michael J","family":"Blackman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,1]]},"reference":[{"key":"BFEMBJ2020107226_CR1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1084\/jem.20050545","volume":"202","author":"AS Aly","year":"2005","unstructured":"Aly AS, Matuschewski K (2005) A malarial cysteine protease is necessary for Plasmodium sporozoite egress from oocysts. 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