{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:52:06Z","timestamp":1791399126582,"version":"4.3.3"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014608","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000}}],"reference-count":90,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bundesministerium f\u00fcr Forschung, Technologie und Raumfahrt","award":["01KI2104"],"award-info":[{"award-number":["01KI2104"]}],"id":[{"id":"https:\/\/ror.org\/04pz7b180","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["531646514"],"award-info":[{"award-number":["531646514"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["446605368"],"award-info":[{"award-number":["446605368"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017519","name":"Werner Otto Stiftung","doi-asserted-by":"publisher","award":["3\/102"],"award-info":[{"award-number":["3\/102"]}],"id":[{"id":"10.13039\/501100017519","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Malaria parasites replicate inside red blood cells, degrading hemoglobin within a specialized digestive vacuole. Efficient hemoglobin processing is essential for parasite survival and influences antimalarial drug susceptibility. The vacuole constantly fuses with incoming hemoglobin-filled vesicles, yet the mechanisms that balance cargo influx with membrane homeostasis remain unclear. Here, using conditional reverse genetics, quantitative live-cell imaging, and 3D electron microscopy, we characterize the autophagy-related protein 18 of\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    (\n                    <jats:italic>Pf<\/jats:italic>\n                    ATG18) as a key regulator of vacuolar membrane dynamics. Loss of\n                    <jats:italic>Pf<\/jats:italic>\n                    ATG18 caused vacuole fragmentation, accumulation of hemoglobin-filled vesicles, and parasite death. These defects were preceded by broad architectural destabilization of the parasite\u2019s V-ATPase, a proton pump controlling organelle acidification and the vacuole\u2019s fusion\u2013fission equilibrium. Direct interference with its membrane sector phenocopied\n                    <jats:italic>Pf<\/jats:italic>\n                    ATG18 deficiency. We found that\n                    <jats:italic>Pf<\/jats:italic>\n                    ATG18 does not interact directly with the proton pump but instead associates with a putative V-ATPase assembly factor and with complexes regulating phosphoinositide balance and vesicle trafficking. The breadth of these interactions indicates a multifaceted role at the vacuolar membrane and a regulatory influence on V-ATPase mediated through associated protein machinery. Although a point mutation in\n                    <jats:italic>Pf<\/jats:italic>\n                    ATG18 has been linked to artemisinin resistance, its complete knockout did not decrease sensitivity. Instead, it rendered ring-stage parasites hypersensitive to dihydroartemisinin, while leaving their susceptibility to other antimalarial drugs unchanged. Together, these findings establish\n                    <jats:italic>Pf<\/jats:italic>\n                    ATG18 as a central regulator of endocytic membrane homeostasis, essential for V-ATPase function and asexual parasite proliferation in the human blood.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014608","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:53:21Z","timestamp":1790618001000},"page":"e1014608","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["PfATG18 links V-ATPase assembly to endocytic membrane dynamics in malaria parasites"],"prefix":"10.1371","volume":"22","author":[{"given":"Yasmin","family":"Schmitz","sequence":"first","affiliation":[{"name":"Molecular Parasitology Group, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moumita","family":"Sengupta","sequence":"additional","affiliation":[{"name":"Molecular Parasitology Group, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Schneider","sequence":"additional","affiliation":[{"name":"Technology platform Microscopy and Image Analysis, Leibniz Institute of Virology","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Ziesmann","sequence":"additional","affiliation":[{"name":"Institute for Immunology, University Medical Center Mainz","place":["Mainz, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Hellmold","sequence":"additional","affiliation":[{"name":"Molecular Parasitology Group, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Distler","sequence":"additional","affiliation":[{"name":"Institute for Immunology, University Medical Center Mainz","place":["Mainz, Germany"]},{"name":"Research Center for Immunotherapy (FZI), University Medical Center Mainz","place":["Mainz, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph","family":"Reimer","sequence":"additional","affiliation":[{"name":"Technology platform Microscopy and Image Analysis, Leibniz Institute of Virology","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0575-0412","authenticated-orcid":true,"given":"Joachim Michael","family":"Matz","sequence":"additional","affiliation":[{"name":"Molecular Parasitology Group, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"issue":"7","key":"ppat.1014608.ref001","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41579-019-0321-3","article-title":"The parasitophorous vacuole of the blood-stage malaria parasite","volume":"18","author":"JM Matz","year":"2020","journal-title":"Nat Rev Microbiol"},{"issue":"4","key":"ppat.1014608.ref002","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1128\/EC.00267-14","article-title":"Defining the morphology and mechanism of the hemoglobin transport pathway in Plasmodium falciparum-infected erythrocytes","volume":"14","author":"KJ Milani","year":"2015","journal-title":"Eukaryot Cell"},{"issue":"2","key":"ppat.1014608.ref003","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0166-6851(01)00427-3","article-title":"Intraerythrocytic Plasmodium falciparum utilizes only a fraction of the amino acids derived from the digestion of host cell cytosol for the biosynthesis of its proteins","volume":"119","author":"M Krugliak","year":"2002","journal-title":"Mol Biochem Parasitol"},{"issue":"6","key":"ppat.1014608.ref004","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.pt.2020.03.010","article-title":"Endocytosis in Plasmodium and Toxoplasma Parasites","volume":"36","author":"T Spielmann","year":"2020","journal-title":"Trends Parasitol"},{"issue":"7","key":"ppat.1014608.ref005","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.pt.2022.02.010","article-title":"Plasmodium\u2019s bottomless pit: Properties and functions of the malaria parasite\u2019s digestive vacuole","volume":"38","author":"JM Matz","year":"2022","journal-title":"Trends Parasitol"},{"issue":"1","key":"ppat.1014608.ref006","doi-asserted-by":"crossref","first-page":"3922","DOI":"10.1038\/s41467-020-17781-6","article-title":"The natural function of the malaria parasite\u2019s chloroquine 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