{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:01:43Z","timestamp":1780290103763,"version":"3.54.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["\u7f16\u53f782072142"],"award-info":[{"award-number":["\u7f16\u53f782072142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["\u7f16\u53f782273934"],"award-info":[{"award-number":["\u7f16\u53f782273934"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["\u7f16\u53f782473928"],"award-info":[{"award-number":["\u7f16\u53f782473928"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>\n                      The p38 MAPK pathway governs the core innate immune response in\n                      <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                      (\n                      <jats:italic>C. elegans<\/jats:italic>\n                      ), yet the negative regulatory networks preventing immune overactivation\u2014and their potential as therapeutic targets\u2014remain elusive. We aimed to identify novel phosphatase checkpoints in host defense, elucidate their molecular mechanisms, and validate their druggability using small-molecule interventions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a genome-wide RNAi screen of 166 phosphatase genes in\n                      <jats:italic>C. elegans<\/jats:italic>\n                      infected with\n                      <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                      (PA14) to identify key regulators. The molecular mechanism was dissected using yeast two-hybrid screening, Co-IP, and mutagenesis assays. Furthermore, a small-molecule screen was performed to identify compounds capable of interfering with PTP-4 function, followed by Surface Plasmon Resonance (SPR), molecular docking, and structural biology approaches to characterize compound\u2013PTP-4 interactions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PTP-4 was identified as a critical negative regulator of immunity. Genetic deficiency of\n                      <jats:italic>ptp-4<\/jats:italic>\n                      significantly enhanced host resistance via hyperactivation of the p38 MAPK (PMK-1) pathway. Mechanistically, PTP-4 physically interacts with ATLN-1, an ER-shaping GTPase, through its phosphatase domain, thereby suppressing immune activation. Crucially, baicalin was identified through compound screening as an inhibitor of\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      infection. Structural and biochemical analyses revealed a dual mechanism of action: baicalin directly binds to the PTP-4\/ATLN-1 interface with high affinity (K\n                      <jats:sub>D<\/jats:sub>\n                      = 28.69\u00a0\u03bcM) to allosterically disrupt their complex formation, while concurrently downregulating PTP-4 protein expression. This \u201cdual-hit\u201d inhibition mimics the genetic loss of\n                      <jats:italic>ptp-4<\/jats:italic>\n                      , effectively unleashing the innate immune response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our study uncovers the PTP-4\/ATLN-1 axis in the control of\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      infection. Importantly, we provide the first proof-of-concept that this axis is a druggable target. By demonstrating that baicalin boosts host immunity through the specific dismantling of the PTP-4\/ATLN-1 complex, we highlight a novel therapeutic strategy for combating bacterial infections.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1804420","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T04:19:22Z","timestamp":1780287562000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphatase PTP-4 downregulates ATLN-1-mediated host defense against Pseudomonas aeruginosa infection in Caenorhabditis elegans"],"prefix":"10.3389","volume":"17","author":[{"given":"Jing","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Shi","sequence":"additional","affiliation":[{"name":"The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwen","family":"Zhong","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoxue","family":"Ge","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/ni.1604","article-title":"Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1","volume":"9","author":"An","year":"2008","journal-title":"Nat. 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