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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,24]]},"abstract":"<jats:p>\n                    Excessive innate immune activation drives uncontrolled inflammation and multiple inflammatory diseases. Proper N-glycosylation of membrane-associated Toll-like receptor 4 (TLR4) is essential for its trafficking to the cell membrane and subsequent innate activation, yet the mechanisms regulating this process remain poorly understood. Through a genome-wide CRISPR screening, we identify calsyntenin-3 (CLSTN3) as a potent suppressor of TLR4-triggered inflammation in macrophages. Mechanistically, CLSTN3 binds to the oligosaccharyltransferase (OST) subunit DDOST, inhibiting its interaction with the catalytic subunit STT3A and impairing OST complex assembly, which reduces N-glycosylation and membrane translocation of TLR4. Furthermore, CLSTN3 also suppresses membrane translocation and activation of other TLRs, including TLR3, TLR7 and TLR9. In addition,\n                    <jats:italic toggle=\"yes\">CLSTN3<\/jats:italic>\n                    expression is reduced in multiple inflammatory diseases and correlates negatively with the cytokine expression in sepsis. Our findings reveal CLSTN3 as a potent suppressor of inflammation by controlling membrane-associated TLR translocation via glycosylation inhibition, presenting a target for intervening inflammatory diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2528269123","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:40:47Z","timestamp":1773855647000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Calsyntenin-3 suppresses inflammation via inhibition of TLR N-glycosylation and membrane localization"],"prefix":"10.1073","volume":"123","author":[{"given":"Jiaqi","family":"Duan","sequence":"first","affiliation":[{"name":"Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, 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