C1ORF106, also named INAVA (Innate Immune Activator), was identified as a risk gene for the chronic inflammatory bowel diseases (IBD) by genome-wide association studies and targeted exome sequencing. INAVA is highly enriched in polarized simple epithelia, the cell type that lines the intestine and interfaces most directly with the outside world. We discover that INAVA provides a direct mechanistic link between mucosal barriers and inflammation. This is driven by INAVA’s signature Domain of Unknown Function DUF3338, which we newly defined as an enhancer of IL-1β-TRAF6 polyubiquitination cascades.