{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T11:35:52Z","timestamp":1773920152082,"version":"3.50.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Cytolethal Distending Toxin (CDT) is the only exotoxin that\n                      <jats:italic>Glaesserella parasuis<\/jats:italic>\n                      (\n                      <jats:italic>G. parasuis<\/jats:italic>\n                      ) can secrete.\n                      <jats:italic>G. parasuis<\/jats:italic>\n                      CDT (\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT) triggers DNA damage responses, leading to irreversible cell cycle arrest and apoptosis, playing an important role in the pathogenic process of\n                      <jats:italic>G. parasuis<\/jats:italic>\n                      . Currently, research on the host cell receptors of\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT remains limited. Screening and identification of host cell receptors that interact with\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT are crucial for systematically elucidating the cytotoxic mechanisms induced by this toxin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study employed Co-immunoprecipitation (Co-IP) combined with Liquid Chromatography-Tandem Mass Spectrometry (LC-MS\/MS) to identify potential host proteins interacting with\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT in PK15 cells. Nine Proteins were selected for further evaluation based on subcellular localization and Gene Ontology classification. Eukaryotic expression and Co-IP validated four interacting proteins. Subsequently, heterozygous knockout PK15 cell lines for these genes were generated via CRISPR\/Cas9, and CCK-8 assays identified TM9SF4 as having the most significant impact on\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT virulence. Therefore, a homozygous\n                      <jats:italic>TM9SF4<\/jats:italic>\n                      knockout PK15 cell line (KO) was generated via limited dilution, and a stable\n                      <jats:italic>TM9SF4<\/jats:italic>\n                      -overexpressing PK15 cell line (OE) was established through lentiviral packaging. Western blotting and qRT-PCR confirmed protein and gene expression, and CCK-8 assays combined with cytopathic effect (CPE) observation determined the role of TM9SF4 in\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT-induced cytotoxicity. Finally, indirect immunofluorescence was performed to assess co-localization of TM9SF4 with\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 287 proteins in PK15 cells that potentially interact with\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT, among which 58 were localized to the plasma membrane or extracellular. Nine proteins were selected for further investigation. Among them, EPHB4, LITAF, TM9SF4, SLC12A4 interacted with\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT, but only the deficiency of TM9SF4 significantly inhibited the virulence of the\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT. Results from CCK-8 and CPE showed that KO cells exhibited significantly higher survival rates and suppressed\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT-induced cellular distention and cell death, whereas OE cells showed decreased survival rates and typical cytopathic change. Finally, indirect immunofluorescence confirmed strong co-localization between TM9SF4 and\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We initially proposed TM9SF4 as a receptor for\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT in PK15 cells,\u00a0essential for\n                      <jats:italic>Gp<\/jats:italic>\n                      CDT binding and cytotoxicity. This study may provide a new\u00a0theoretical basis for targeted prevention and treatment of swine Gl\u00e4sser\u2019s disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1783709","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:47:48Z","timestamp":1773902868000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TM9SF4 acts as a receptor mediating Glaesserella parasuis cytolethal distending toxin\u2013induced cytotoxicity in PK15 cells"],"prefix":"10.3389","volume":"16","author":[{"given":"Li","family":"Lei","sequence":"first","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu Agricultural Science and Technology Center","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Yang","sequence":"additional","affiliation":[{"name":"Chongqing Academy of Animal Sciences","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyu","family":"Pan","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiali","family":"Xu","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Senyan","family":"Du","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobo","family":"Huang","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjie","family":"Cao","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Wu","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiping","family":"Wang","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qigui","family":"Yan","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiping","family":"Wen","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3325","DOI":"10.1242\/jcs.030163","article-title":"TM9SF4 is required for Drosophila cellular immunity via cell adhesion and phagocytosis","volume":"121","author":"Bergeret","year":"2008","journal-title":"J. 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