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Alliance"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:p>Monosodium uric acid (MSU) crystal, the etiological agent of gout, has been shown to trigger innate immune responses via multiple pathways. It is known that MSU-induced lipid sorting on plasma membrane promotes the phosphorylation of Syk and eventually leads to the activation of phagocytes. However, whether this membrane lipid-centric mechanism is regulated by other processes is unclear. Previous studies showed that Clec12a, a member of the C-type lectin receptor family, is reported to recognize MSU and suppresses this crystalline structure-induced immune activation. How this scenario is integrated into the lipid sorting-mediated inflammatory responses by MSU, and particularly, how Clec12a intercepts lipid raft-originated signaling cascade remains to be elucidated. Here, we found that the ITIM motif of Clec12a is dispensable for its inhibition of MSU-mediated signaling; instead, the transmembrane domain of Clec12a disrupts MSU-induced lipid raft recruitment and thus attenuates downstream signals. Single amino acid mutagenesis study showed the critical role of phenylalanine in the transmembrane region for the interactions between C-type lectin receptors and lipid rafts, which is critical for the regulation of MSU-mediated lipid sorting and phagocyte activation. Overall, our study provides new insights for the molecular mechanisms of solid particle-induced immune activation and may lead to new strategies in inflammation control.<\/jats:p>","DOI":"10.26508\/lsa.202301938","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T12:40:13Z","timestamp":1687264813000},"page":"e202301938","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Clec12a inhibits MSU-induced immune activation through lipid raft expulsion"],"prefix":"10.26508","volume":"6","author":[{"given":"Ying","family":"Xu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Immunology, School of Medicine, Tsinghua University","place":[", Beijing, 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