Genome-wide association studies (GWAS) have identified over 40 non-HLA susceptibility loci for celiac disease (CeD), yet the function of most associated genes remains unknown. We recently demonstrated that dysregulation of the RNA modification machinery contributes to intestinal inflammation in CeD, highlighting RNA regulatory pathways as emerging mediators of disease. Here, we investigated the role of PUS10, an RNA pseudouridine synthase encoded within a CeD susceptibility locus, in epithelial inflammatory responses.
PUS10 protein expression was significantly reduced in duodenal biopsies from patients with active CeD compared with non-CeD controls. Silencing of PUS10 in intestinal epithelial cells induced a broad inflammatory program characterized by activation of type I interferon and innate immune pathways, accompanied by increased inflammatory mediators relevant to CeD, including IL-6, IL-7 and IL-15 and the antigen presentation pathway. Importantly, conditioned media from PUS10-deficient epithelial cells promoted T cell activation, demonstrating that epithelial PUS10 deficiency is sufficient to enhance epithelial–immune crosstalk. Consistent with these findings, CRISPR-engineered epithelial cells carrying the CeD-associated PUS10 risk allele exhibited enhanced inflammatory responses following stimulation, providing functional evidence that disease-associated genetic variation at this locus modulates epithelial immune signaling.
Together, these findings identify PUS10 as a previously unrecognized regulator of epithelial inflammatory programming in CeD and establish a functional link between a CeD susceptibility locus and epithelial-driven immune activation. Our study provides the first functional characterization of PUS10 in celiac disease and reveals a novel mechanism through which genetic susceptibility may promote intestinal inflammation, further supporting RNA regulatory pathways as key contributors to CeD pathogenesis.