Sphingomyelin synthase 2 deficiency suppresses airway mucus accumulation by altering sphingolipid flux and mucin glycosylation.

Sphingomyelin synthase 2 (SMS2) produces sphingomyelin from ceramide. In this study, SMS2 deficiency reduced airway accumulation of glycosylated mucins, such as MUC5AC, in a murine model of asthma, prompting investigation of the molecular mechanisms in mucin-forming epithelial cells. In the cell model, SMS2 silencing promoted the conversion of ceramide to glucosylceramide, a precursor of complex glycosphingolipids. This alteration reduced MUC5AC glycosylation, suggesting the potential for biochemical competition between sphingolipids and MUC5AC for glycosylation. Supplying C6-ceramide, which increases biochemical glycosylation for sphingolipids, reduced glycosylated MUC5AC, but this effect was absent in glucosylceramide synthase-silenced cells. These findings indicate that SMS2 deficiency alters sphingolipid metabolism, reducing MUC5AC glycosylation and maturation, underscoring the role of sphingolipid dynamics in modulating mucus production.