{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:24:39Z","timestamp":1790141079386,"version":"4.0.1"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>P-Rex1 is a guanine-nucleotide factor for the small GTPase Rac (Rac-GEF) that is known to mediate neutrophil migration and ROS production in response to the activation of GPCRs. These roles of P-Rex1 are assumed to require its activation of Rac.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we used mice which lack P-Rex1 (<jats:italic>Prex1<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup>) and mice with catalytically inactive P-Rex1 (<jats:italic>Prex1<jats:sup>GD<\/jats:sup><\/jats:italic>) to investigate the importance of the Rac-GEF activity in migration and ROS production. We also studied the requirement for P-Rex1 in degranulation, phagocytosis, NET formation, and the bactericidal activity of neutrophils.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that P-Rex1 mediates migration, ROS, and NETs through its Rac-GEF activity, but is dispensable for the degranulation of azurophil, specific and gelatinase granules. Surprisingly, P-Rex1 mediates the clearance of bacteria <jats:italic>in vivo<\/jats:italic> during septic peritonitis and the killing of bacteria by isolated neutrophils independently of its catalytic Rac-GEF activity. P-Rex1 also mediates the phagocytosis of IgG-opsonized zymosan yeast particles independently of its catalytic Rac-GEF activity. P-Rex1 is required for both integrin-dependent and Fc receptor-dependent phagocytosis, and it mediates the Fc receptor-dependent activation of Rac and Syk. Recently identified adaptor functions of P-Rex1 in GPCR trafficking and glucose uptake do not seem to underlie its GEF-activity independent roles in neutrophils.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Together, our study identifies P-Rex1 as a regulator of NET formation and phagocytosis in neutrophils and reveals that P-Rex1 mediates bactericidal activity and phagocytosis independently of its catalytic Rac-GEF activity, through mechanisms not obviously linked to other recently identified adaptor functions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1591006","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T05:37:16Z","timestamp":1759210636000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["P-Rex1 controls phagocytosis and the killing of bacteria by murine neutrophils independently of its catalytic activity"],"prefix":"10.3389","volume":"16","author":[{"given":"Priota","family":"Islam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Y.","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Chetwynd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip T.","family":"Hawkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi C. 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