The Ulcerative Colitis-Associated Gene NXPE1 Catalyzes Glycan Modifications on Colonic Mucin

Area of Science:

• Biochemistry
• Microbiology
• Gastroenterology

Background:

• Colonic mucus is a critical defense barrier and nutrient source for gut microbes.
• Mucin proteins undergo extensive post-translational modifications, but the enzymes involved are not fully understood.
• NXPE1 is a gene linked to ulcerative colitis (UC), suggesting a role in gut health.

Purpose of the Study:

• To determine the biochemical function of the NXPE1 gene.
• To investigate NXPE1's role in mucin modification and its implications for UC.

Main Methods:

• Biochemical assays to characterize NXPE1 enzymatic activity.
• Analysis of colonic organoids from donors with different NXPE1 variants.
• Mass spectrometry to identify modified mucin glycans.

Main Results:

• NXPE1 encodes an acetyltransferase that regioselectively acetylates sialic acid (Neu5Ac) on mucins at the 9-OH position, forming Neu5,9Ac2.
• A UC-protective NXPE1 variant (G353R) significantly impairs mucin acetylation in colonic organoids.
• NXPE1-mediated acetylation masks alcohol groups on mucus sialoglycans.

Conclusions:

• NXPE1 plays a key role in modifying colonic mucins through acetylation.
• This modification is essential for regulating mucus barrier properties and interactions with commensal microbes.
• Dysfunctional NXPE1 activity, particularly the G353R variant, is associated with impaired mucin acetylation and may contribute to UC pathogenesis.