{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T15:13:40Z","timestamp":1782141220716,"version":"3.54.5"},"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["400\/22"],"award-info":[{"award-number":["400\/22"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2786\/22"],"award-info":[{"award-number":["2786\/22"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["301\/21"],"award-info":[{"award-number":["301\/21"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    The apicoplast of\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    parasites serves as a metabolic hub that synthesize essential biomolecules. Like other endosymbiotic organelles, 90% of the apicoplast proteome is encoded by the cell nucleus and transported to the organelle. Evidence suggests that the apicoplast has minimal control over the synthesis of its proteome and therefore it is unclear how organelle proteostasis is regulated. Here, we identified and investigated a large and conserved chaperonin (CPN) complex with a previously unknown function. Using genetic tools, we demonstrated that ablation of the apicoplast CPN60 subunit leads to parasite death due to organellar damage, immediately within its first replication cycle, deviating from the delayed death phenotype commonly observed for apicoplast translation inhibitors. Unlike its close orthologues in other prokaryotic and eukaryotic cells, CPN60 is not upregulated during heat shock (HS) and does not affect HS response in the parasite. Instead, we found that it is directly involved in proteostasis through interaction with the Clp (caseinolytic protease) proteolytic complex. We showed that CPN60 physically binds both the active and inactive forms of the Clp complex, and manipulates its stability. A computational structural model of a possible interaction between these two large complexes suggests a stable interface. Finally, we screened a panel of inhibitors for the bacterial CPN60 orthologue GroEL, to test the potential of chaperonin inhibition as antimalarial. These inhibitors demonstrated an anti-\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    activity that was not restricted to apicoplast function, with additional targets outside of this organelle. Taken together, this work reveals how balanced activities of proteolysis and refolding safeguard the apicoplast proteome, and are essential for organelle biogenesis.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013275","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T17:22:33Z","timestamp":1753204953000},"page":"e1013275","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["A chaperonin complex regulates organelle proteostasis in malaria parasites"],"prefix":"10.1371","volume":"21","author":[{"given":"Amanda","family":"Tissawak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yarden","family":"Rosin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirly","family":"Katz Galay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alia","family":"Qasem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Shahar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirit","family":"Trabelsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ora","family":"Furman-Schueler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9071-0078","authenticated-orcid":true,"given":"Anat","family":"Florentin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"issue":"3","key":"ppat.1013275.ref001","doi-asserted-by":"crossref","DOI":"10.1016\/S2666-5247(24)00016-8","article-title":"The 2023 WHO World malaria report","volume":"5","author":"P Venkatesan","year":"2024","journal-title":"Lancet Microbe"},{"issue":"6582","key":"ppat.1013275.ref002","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/381482a0","article-title":"Plastid in human parasites","volume":"381","author":"GI McFadden","year":"1996","journal-title":"Nature"},{"issue":"5305","key":"ppat.1013275.ref003","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1126\/science.275.5305.1485","article-title":"A plastid of probable green algal origin in Apicomplexan parasites","volume":"275","author":"S K\u00f6hler","year":"1997","journal-title":"Science"},{"key":"ppat.1013275.ref004","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1146\/annurev-micro-092412-155741","article-title":"The algal past and parasite present of the apicoplast","volume":"67","author":"GG van Dooren","year":"2013","journal-title":"Annu Rev Microbiol"},{"issue":"3","key":"ppat.1013275.ref005","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nrmicro843","article-title":"Tropical infectious diseases: metabolic maps and functions of the Plasmodium falciparum apicoplast","volume":"2","author":"SA Ralph","year":"2004","journal-title":"Nat Rev Microbiol"},{"issue":"6658","key":"ppat.1013275.ref006","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/37132","article-title":"A plastid organelle as a drug target in apicomplexan parasites","volume":"390","author":"ME Fichera","year":"1997","journal-title":"Nature"},{"issue":"4","key":"ppat.1013275.ref007","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1042\/BST20170563","article-title":"Targeting the apicoplast in malaria","volume":"47","author":"M Biddau","year":"2019","journal-title":"Biochem Soc Trans"},{"issue":"8","key":"ppat.1013275.ref008","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1093\/emboj\/19.8.1794","article-title":"Protein trafficking to the plastid of Plasmodium falciparum is via the secretory pathway","volume":"19","author":"RF Waller","year":"2000","journal-title":"EMBO J"},{"issue":"5607","key":"ppat.1013275.ref009","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1126\/science.1078599","article-title":"Dissecting apicoplast targeting in the malaria parasite Plasmodium falciparum","volume":"299","author":"BJ Foth","year":"2003","journal-title":"Science"},{"issue":"2","key":"ppat.1013275.ref010","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1008316","article-title":"A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites","volume":"16","author":"RP Swift","year":"2020","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1013275.ref011","article-title":"Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum","volume":"9","author":"E Yeh","year":"2011","journal-title":"PLoS Biol"},{"issue":"1","key":"ppat.1013275.ref012","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02021-17","article-title":"ATG8 Is Essential Specifically for an Autophagy-Independent Function in Apicoplast Biogenesis in Blood-Stage Malaria Parasites","volume":"9","author":"M Walczak","year":"2018","journal-title":"mBio"},{"issue":"16","key":"ppat.1013275.ref013","doi-asserted-by":"crossref","DOI":"10.15252\/embj.2020107247","article-title":"Dephospho-CoA kinase, a nuclear-encoded apicoplast protein, remains active and essential after Plasmodium falciparum apicoplast disruption","volume":"40","author":"RP Swift","year":"2021","journal-title":"EMBO J"},{"issue":"7","key":"ppat.1013275.ref014","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1016\/j.celrep.2017.10.081","article-title":"PfClpC Is an Essential Clp Chaperone Required for Plastid Integrity and Clp Protease Stability in Plasmodium falciparum","volume":"21","author":"A Florentin","year":"2017","journal-title":"Cell Rep"},{"issue":"24","key":"ppat.1013275.ref015","doi-asserted-by":"crossref","first-page":"13719","DOI":"10.1073\/pnas.1919501117","article-title":"Plastid biogenesis in malaria parasites requires the interactions and catalytic activity of the Clp proteolytic 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Bouchnak","year":"2021","journal-title":"J Biol Chem"},{"issue":"6","key":"ppat.1013275.ref019","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1105\/tpc.111.086454","article-title":"Subunit stoichiometry, evolution, and functional implications of an asymmetric plant plastid ClpP\/R protease complex in Arabidopsis","volume":"23","author":"PDB Olinares","year":"2011","journal-title":"Plant Cell"},{"issue":"6","key":"ppat.1013275.ref020","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1105\/tpc.108.063784","article-title":"Subunits of the plastid ClpPR protease complex have differential contributions to embryogenesis, plastid biogenesis, and plant development in Arabidopsis","volume":"21","author":"J Kim","year":"2009","journal-title":"Plant Cell"},{"issue":"2","key":"ppat.1013275.ref021","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1074\/jbc.M112.416560","article-title":"Structural insights into the inactive subunit of the apicoplast-localized 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