biostudies-literatureGovindan ANIAID NIH HHSNCI NIH HHSNational Institutes of HealthNIH HHSNIGMS NIH HHSRP104439https://www.ebi.ac.uk/biostudies/studies/S-EPMC12017769biostudies-literatureUnknown13O-GlcNAcylation is the reversible post-translational addition of β-<i>N</i>-acetylglucosamine to serine and threonine residues of nuclear and cytoplasmic proteins. It plays an important role in several cellular processes through the modification of thousands of protein substrates. O-GlcNAcylation in humans is mediated by a single essential enzyme, O-GlcNAc transferase (OGT). OGT, together with the sole O-GlcNAcase OGA, form an intricate feedback loop to maintain O-GlcNAc homeostasis in response to changes in cellular O-GlcNAc using a dynamic mechanism involving nuclear retention of its fourth intron. However, the molecular mechanism of this dynamic regulation remains unclear. Using an O-GlcNAc responsive GFP reporter cell line, we identify SFSWAP, a poorly characterized splicing factor, aseLifeSFSWAP is a negative regulator of OGT intron detention and global pre-mRNA splicing.PMC12017769R01 GM127311U01 CA242115R01 AI153175R01 AI123165Govindan AConrad NKfalseSFSWAP is a negative regulator of OGT intron detention and global pre-mRNA splicing.O-GlcNAcylation is the reversible post-translational addition of β-<i>N</i>-acetylglucosamine to serine and threonine residues of nuclear and cytoplasmic proteins. It plays an important role in several cellular processes through the modification of thousands of protein substrates. O-GlcNAcylation in humans is mediated by a single essential enzyme, O-GlcNAc transferase (OGT). OGT, together with the sole O-GlcNAcase OGA, form an intricate feedback loop to maintain O-GlcNAc homeostasis in response to changes in cellular O-GlcNAc using a dynamic mechanism involving nuclear retention of its fourth intron. However, the molecular mechanism of this dynamic regulation remains unclear. Using an O-GlcNAc responsive GFP reporter cell line, we identify SFSWAP, a poorly characterized splicing factor, as2025-01-01T00:00:00Z2025 Apr2026-07-15T11:03:39.645Z2025-07-02T03:04:46.034ZS-EPMC120177694026557110.7554/eLife.104439