{
  "abstract": "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 Plasmodium falciparum (PfATG18) as a key regulator of vacuolar membrane dynamics. Loss of PfATG18 caused vacuole fragmentation, accumulation of hemoglobin-filled vesicles, and parasite death. These defects were preceded by broad architectural destabilization of the parasite’s V-ATPase, a proton pump controlling organelle acidification and the vacuole’s fusion–fission equilibrium. Direct interference with its membrane sector phenocopied PfATG18 deficiency. We found that PfATG18 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 PfATG18 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 PfATG18 as a central regulator of endocytic membrane homeostasis, essential for V-ATPase function and asexual parasite proliferation in the human blood. Author summary: Malaria parasites cause disease by multiplying inside human red blood cells, where they consume hemoglobin, the oxygen-carrying protein of the host cell. Hemoglobin is taken up in vesicles and delivered to a specialized digestive vacuole, where it is broken down to support parasite growth and survival. In this study, we characterized the function of PfATG18, a protein associated with the vacuolar membrane. We found that PfATG18 is essential for keeping the digestive vacuole intact and ensuring its efficient fusion with incoming hemoglobin-containing vesicles. When PfATG18 is inactivated, a protein complex required for vacuole acidification and membrane stability called V-ATPase, becomes destabilized and disassembles. Although PfATG18 does not directly interact with the V-ATPase, it associates with proteins involved in V-ATPase assembly, lipid regulation, and vesicle trafficking, indicating a broader role in coordinating processes at the vacuolar membrane. We also found that loss of PfATG18 increases the sensitivity of young blood-stage parasites to antimalarial drug treatment. Together, our findings identify PfATG18 as a key regulator of digestive vacuole function and parasite survival, providing new insight into a critical vulnerability of the malaria parasite.",
  "abstract_shown": true,
  "affiliations": [
    "Molecular Parasitology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany",
    "Technology platform Microscopy and Image Analysis, Leibniz Institute of Virology, Hamburg, Germany",
    "Institute for Immunology, University Medical Center Mainz, Mainz, Germany",
    "Research Center for Immunotherapy (FZI), University Medical Center Mainz, Mainz, Germany"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yasmin Schmitz"
    },
    {
      "affs": [
        1
      ],
      "name": "Moumita Sengupta"
    },
    {
      "affs": [
        2
      ],
      "name": "Carola Schneider"
    },
    {
      "affs": [
        3
      ],
      "name": "Tanja Ziesmann"
    },
    {
      "name": "Franziska Hellmold"
    },
    {
      "name": "Ute Distler"
    },
    {
      "name": "Rudolph Reimer"
    },
    {
      "name": "Joachim Michael Matz"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7hxn8tfa1q1zy.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.ppat.1014608",
  "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014608",
  "id": "7hxn8tfa1q1zy",
  "issns": [
    "1553-7374"
  ],
  "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014608",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2739|Malaria Research and Control"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Hemoglobin"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Vacuoles"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Vesicles"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/Red blood cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cytosol"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Virology/Viral transmission and infection/Host cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Eukaryota/Protozoans/Parasitic protozoans/Malarial parasites"
    ],
    [
      "plos",
      "/Biology and life sciences/Parasitology/Parasite replication"
    ]
  ],
  "openalex": "W7214586255",
  "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014608&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-28",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/7hxn8tfa1q1zy.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:37Z",
      "native_id": "10.1371/journal.ppat.1014608",
      "source": "plos",
      "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014608"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "plos:virology",
      "subfield": "microbiology"
    }
  ],
  "title": "PfATG18 links V-ATPase assembly to endocytic membrane dynamics in malaria parasites",
  "title_text": "PfATG18 links V-ATPase assembly to endocytic membrane dynamics in malaria parasites",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:37Z",
  "url": "https://research.draconitic.com/paper/7hxn8tfa1q1zy",
  "venue": "PLOS Pathogens",
  "versions": []
}