{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:53:08Z","timestamp":1789908788331,"version":"4.0.1"},"reference-count":70,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["ZIA AI000882-25"],"award-info":[{"award-number":["ZIA AI000882-25"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Division of Intramural Research, NIAID\/NIH","award":["Training Award"],"award-info":[{"award-number":["Training Award"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>To grow and replicate in erythrocytes, malaria parasites must increase the host cell\u2019s permeability to a broad range of nutrients. The plasmodial surface anion channel (PSAC) mediates this increased permeability and has been linked to CLAG3, a protein encoded by a multigene family conserved in <jats:italic><jats:italic>Plasmodium spp.<\/jats:italic><\/jats:italic> Surprisingly, an CLAG3 knockout parasite produced in <jats:italic><jats:italic>P. falciparum<\/jats:italic><\/jats:italic> exhibits incomplete reductions in PSAC activity, propagates normally in standard nutrient-rich media, but is unable to expand in modified media with more physiological levels of key nutrients. To explore these unexpected findings, we used <jats:italic><jats:italic>in vitro<\/jats:italic><\/jats:italic> selections on a CLAG3-null parasite and obtained a mutant capable of expansion under nutrient-limiting conditions. This growth was associated with restored solute uptake despite absence of CLAG3 protein. The mutant parasite expressed channels with characteristics of PSAC though with altered solute selectivity and lack of protease susceptibility, suggesting a modified channel and genome-level changes in the pathogen. Whole-genome sequencing revealed a dramatically increased <jats:italic><jats:italic>clag2<\/jats:italic><\/jats:italic> copy number without other relevant changes. Quantitative PCR and DNA transfection confirmed increased production of the <jats:italic><jats:italic>clag2<\/jats:italic><\/jats:italic> gene product. These findings implicate CLAG2 in direct formation of nutrient channels, suggest a new model that accounts for variable expansion of <jats:italic><jats:italic>clag<\/jats:italic><\/jats:italic> genes in <jats:italic><jats:italic>Plasmodium spp.<\/jats:italic><\/jats:italic>, and uncover a dramatic genome plasticity available to malaria parasites.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013321","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T17:45:31Z","timestamp":1760636731000},"page":"e1013321","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nutrient stress dramatically increases malaria parasite clag2 copy number to increase host cell permeability and enable pathogen survival"],"prefix":"10.1371","volume":"21","author":[{"given":"Nicole B.","family":"Potchen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiane Macedo","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inderjeet","family":"Kalia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin B.","family":"Lack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2150-2483","authenticated-orcid":true,"given":"Sanjay A.","family":"Desai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"issue":"2","key":"ppat.1013321.ref001","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.chom.2017.07.003","article-title":"The Molecular Basis of Erythrocyte Invasion by Malaria 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Baumeister","year":"2006","journal-title":"Mol Microbiol"},{"issue":"4","key":"ppat.1013321.ref036","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0093759","article-title":"Proteolysis at a specific extracellular residue implicates integral membrane CLAG3 in malaria parasite nutrient channels","volume":"9","author":"W Nguitragool","year":"2014","journal-title":"PLoS One"},{"issue":"5153","key":"ppat.1013321.ref037","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/219529a0","article-title":"Permeability of erythrocytes to anions and the regulation of cell volume","volume":"219","author":"A Scarpa","year":"1968","journal-title":"Nature"},{"issue":"6799","key":"ppat.1013321.ref038","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/35023000","article-title":"A voltage-dependent channel involved in nutrient uptake by red blood cells infected with the malaria parasite","volume":"406","author":"SA 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