Deficiency of AP1M2 Causes a New Autoinflammatory Disease With Colitis.
OBJECTIVE: This study was the first to identify the biallelic loss-of-function variant in AP1M2 as the cause of autoinflammatory disease with colitis and aimed to elucidate the pathogenesis of AP1M2 deficiency in mice and humans. METHODS: We collected a blood sample and serum sample from a patient for genetic diagnosis and determination of inflammatory cytokines, respectively. Ap1m2-deficient mice on the C57BL/6 background and DLD-1 cells were used to dissect the functional role of Ap1m2 in serum and intestines. Stereo-seq was performed on Ap1m2-/- and Ap1m2-/-::Tnfr1-/- mouse samples to investigate the regulatory role of Tnfr1 signaling in the pathogenesis of Ap1m2 deficiency-caused intestinal inflammation. Superrevolution imaging and clathrin-coated vesicle enrichment were used to explore the molecular mechanism by which AP1M2 suppresses NF-κB activation and chemokine production. RESULTS: Ap1m2-/- mice exhibited elevated chemokine production in serum and spontaneously developed intestinal inflammation, which phenocopies the patient with the AP1M2 variant. Mechanistically, the deficiency of intestinal epithelial specific AP1M2 expression resulted in accumulation of TNFR1-signaling downstream proteins, including RIPK1, TBK1, IKKα/β, and NEMO, leading to enhanced NF-κB activation and subsequent chemokine overproduction. Tnfr1 knockout rescued gastrointestinal inflammation induced by Ap1m2 deficiency through suppressing NF-κB activation and chemokine production. CONCLUSION: This study identifies the deficiency of AP1M2 as the cause of a new autoinflammatory disease with colitis and highlights the critical function of AP-1 in suppressing NF-κB activation and chemokine production.