{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T04:15:58Z","timestamp":1751948158226,"version":"3.41.2"},"reference-count":85,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372280 AND 81971961"],"award-info":[{"award-number":["82372280 AND 81971961"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012131","name":"Department of Science and Technology of Liaoning province","doi-asserted-by":"crossref","award":["2022-MS-239"],"award-info":[{"award-number":["2022-MS-239"]}],"id":[{"id":"10.13039\/501100012131","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19AI089672"],"award-info":[{"award-number":["U19AI089672"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI150533-01"],"award-info":[{"award-number":["R01 AI150533-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Protein phosphorylation plays a critical role during the development of malaria parasites. Here, we performed a functional analysis of the <jats:italic>Plasmodium berghei<\/jats:italic> Ser\/Thr protein phosphatase 6 (PbPP6), which is associated with the plasma membrane of macrogametes and ookinetes. Compared to wild-type <jats:italic>P. berghei<\/jats:italic>, the genetic disruption of <jats:italic>pbpp6<\/jats:italic> (\u2206<jats:italic>pbpp6<\/jats:italic>) resulted in reduced asexual growth of the parasites and prolonged survival of infected mice. The \u2206<jats:italic>pbpp6<\/jats:italic> parasites showed impaired gametogenesis, particularly affecting male gametogenesis, which substantially decreased both ookinete formation and mosquito transmission. Transcriptomic analysis revealed an over 11-fold downregulation of <jats:italic>nek3<\/jats:italic>, a regulator of MAPK2 within the PKG-Ca<jats:sup>2<\/jats:sup>\u207a\u2009signaling cascade, foreshadowing pathway dysregulation that was further evidenced by significantly diminished intracellular cGMP levels, decreased cytosolic Ca<jats:sup>2<\/jats:sup>\u207a\u2009mobilization, and reduced DNA replication in activated \u0394<jats:italic>pbpp6<\/jats:italic> gametocytes. Phosphoproteomic analysis detected increased phosphorylation at the Ser508 site of guanylyl cyclase alpha (GC\u03b1), indicating that PbPP6 regulates cGMP-PKG-Ca<jats:sup>2+<\/jats:sup> signaling through modulation of GC\u03b1 activity during gametogenesis. Additionally, we observed altered expression of messenger ribonucleoproteins in the \u0394<jats:italic>pbpp6<\/jats:italic> parasites, which may affect the translational repression of stored mRNAs in female gametocytes and impact post-fertilization development in mosquitoes. Collectively, this study highlights the potential of targeting PP6 to disrupt malaria transmission.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013318","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T17:48:12Z","timestamp":1751910492000},"page":"e1013318","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of serine\/threonine protein phosphatase 6 severely impairs sexual stage development in malaria parasite Plasmodium berghei"],"prefix":"10.1371","volume":"21","author":[{"given":"Yonghui","family":"Feng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuangrui","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liying","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwang","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaming","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9064-586X","authenticated-orcid":true,"given":"Xiaotong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"ppat.1013318.ref001","first-page":"32","volume-title":"Global 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