{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T23:24:20Z","timestamp":1793748260130,"version":"4.6.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T00:00:00Z","timestamp":1718582400000},"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. Immunol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO<jats:sub>2<\/jats:sub>) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO<jats:sub>2<\/jats:sub> controlled MC degranulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>HMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO<jats:sub>2<\/jats:sub> content was detected by <jats:italic>in situ<\/jats:italic> fluorescent probe. MC degranulation represented by the release rate of MC \u03b2-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS\/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO<jats:sub>2<\/jats:sub>. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO<jats:sub>2<\/jats:sub> on mast cell activation <jats:italic>in vivo<\/jats:italic>. Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO<jats:sub>2<\/jats:sub> and support the significance of SO<jats:sub>2<\/jats:sub>\/Gal-9 signal axis in the regulation of MC degranulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Degranulation was increased in AAT1-knockdowned MCs, and SO<jats:sub>2<\/jats:sub> supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO<jats:sub>2<\/jats:sub> contributed to IgE-mediated degranulation <jats:italic>in vitro.<\/jats:italic> Besides, SO<jats:sub>2<\/jats:sub> inhibited IgE-mediated and hypoxia-driven MC degranulation <jats:italic>in vivo<\/jats:italic>. Mechanistically, LC-MS\/MS analysis and site-directed mutation results showed that SO<jats:sub>2<\/jats:sub> sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74<jats:sup>th<\/jats:sup> cysteine of Gal-9 protein was required in the SO<jats:sub>2<\/jats:sub>-inhibited MC degranulation under both physiological and pathophysiological conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings elucidated that SO<jats:sub>2<\/jats:sub> inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1369326","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T04:38:32Z","timestamp":1718599112000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Sulfur dioxide inhibits mast cell degranulation by sulphenylation of galectin-9 at cysteine 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