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

Year: 2026

Type: article

Abstract: Background & Aims Tumor necrosis factor (TNF) is a key driver of intestinal epithelial inflammation. The baculoviral inhibitor of apoptosis protein repeat-containing 3 ( BIRC3 ) gene encodes the cellular inhibitor of apoptosis protein 2 (cIAP2), a known regulator of TNF signaling. Although genetic variants in components of the TNF signaling pathway have been reported, no human BIRC3 variants have been previously identified. Methods We screened exomes obtained from Crohn's disease (CD) patients from multiple centers for BIRC3 variants. We used cellular, mouse organoids, induced pluripotent stem cells–derived intestinal organoids, knock-in and knockout mouse models, and knockout zebrafish, as well as transcriptome analysis of various samples to determine pathogenicity of BIRC3 variants. Results Rare and damaging BIRC3 variants were identified in 14 patients from 10 unrelated families with CD diagnosed between infancy and adulthood. Functional studies showed that BIRC3 deficiency caused impaired receptor-interacting protein kinase 1 (RIPK1) ubiquitylation, leading to RIPK1 autophosphorylation resulting in increased epithelial cell death. The p.H312Y cIAP2 variant identified in both our index and in another independent patient was mislocalizaed, and a knock-in mouse model of this BIRC3 variant (cIAP2 H312Y/+ ) had exacerbation of chemically induced colitis, whereas ciap1 −/+ zebrafish developed spontaneous colitis. Transcriptome analysis of mice organoids and zebrafish showed that BIRC3 deficiency led to inappropriate sustained activation of TNF-responsiveness genes in the absence of stimuli. Small molecule pharmacologic inhibition of RIPK1 or caspases attenuated intestinal inflammation in BIRC3 -deficient intestinal organoids and cIAP2 H312Y/+ mice. Conclusions We establish BIRC3 deficiency as a cause of monogenic CD in both pediatric- and adult-onset patients and identify RIPK1 as a therapeutic target.

Source: Gastroenterology

DOI: 10.1053/j.gastro.2026.05.022

Institutions: Hospital for Sick Children, Saitama Children's Medical Center, East China Normal University, Ludwig-Maximilians-Universität München, Icahn School of Medicine at Mount Sinai, Michigan Medicine, Inserm, Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Louis, Institut des Maladies Génétiques Imagine, Rockefeller University, China Medical University, Boston Children's Hospital, Harvard University, Cedars-Sinai Medical Center, King Saud University, Hôpital Necker-Enfants Malades, Children's Medical Center, The University of Texas Southwestern Medical Center, Tohoku University, Southern Medical University, Hospital Infantil Universitario Niño Jesús, Clemenshospital Münster, LMU Klinikum, Brigham and Women's Hospital, Howard Hughes Medical Institute, Children's Hospital Colorado, University of Colorado Anschutz, Helmholtz Munich, University of Toronto

Language: English

Topic: Inflammatory Bowel Disease

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,180

Funders: Leona M. and Harry B. Helmsley Charitable Trust, Canadian Institutes of Health Research, National Institute of Diabetes and Digestive and Kidney Diseases

Awards: Role of Interferon lambda signaling in mucosal homeostasis and infantile-onset inflammatory bowel disease, Identifying Immune and Epithelial Network Signatures in Very Early Onset Inflammatory Bowel Disease, Determining genomic and host-environment contributions to IBD phenotypes, COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository

OpenAlex ID: W7165665087