BIRC3 (Encoding cIAP2) Variants Result in Dysregulated RIPK1 Signaling Leading to Increased Epithelial Cell Death and Are Associated With Monogenic Crohn's Disease.

Rare, damaging BIRC3 variants were found in 14 Crohn’s disease patients from 10 unrelated families, and BIRC3 deficiency dysregulated RIPK1 signaling to increase epithelial cell death.

• Why it matters: TNF-driven intestinal epithelial inflammation is central to Crohn’s disease, but human BIRC3 variants and their pathogenic mechanism were previously unidentified.
• What they did: Exome screening across multiple centers identified BIRC3 variants, and functional testing in cellular systems, mouse and iPSC-derived intestinal organoids, knock-in/out mice, and knockout zebrafish assessed RIPK1 ubiquitylation, TNF-responsive transcription, and drug sensitivity.
• The result: BIRC3 deficiency impaired RIPK1 ubiquitylation, promoting RIPK1 autophosphorylation and increased epithelial cell death; RIPK1 or caspase inhibition attenuated inflammation in BIRC3-deficient organoids and cIAP2 H312Y/+ mice.

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