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

Qi Li; Ryusuke Nambu; Hu Yaqiang; Xiang Shen; Carmen Argmann; Rei Guan; Erin Janssen; Tom Le Voyer; Neil Warner; Daniel D Yu; Jing Guo; Kelvin Long; Jodie Ouahed; Michael Field; Lauren Collen; Jonas Bibus; David Illig; Meino Rohlfs; Ziqi Yu; Shaohong Yang; Wenjuan Li; Craig D Platt; Phillip H Comella; Daniel Jordan; Mayte Suárez-Fariñas; Mohammed F Alosaimi; Lauren A Peters; Jeremie Rosain; Claire Fieschi; Anne Puel; Elena W Y Hsieh; Takeo Naito; Zhiyang Zeng; Marta Velasco Rodríguez-Belvís; Laura Palomino; Peter Küster; Dalin Li; Christoph Klein; Scott B Snapper; Jean-Laurent Casanova; Raif Geha; Edward Hoffenberg; Dermot P B McGovern; Eric Schadt; Daniel Kotlarz; Dali Li; Aleixo M Muise

doi:10.1053/j.gastro.2026.05.022

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

Gastroenterology. 2026 Jun 23:S0016-5085(26)06946-5. doi: 10.1053/j.gastro.2026.05.022. Online ahead of print.

Authors

Qi Li¹, Ryusuke Nambu², Hu Yaqiang³, Xiang Shen⁴, Carmen Argmann⁵, Rei Guan¹, Erin Janssen⁶, Tom Le Voyer⁷, Neil Warner¹, Daniel D Yu¹, Jing Guo⁸, Kelvin Long¹, Jodie Ouahed⁹, Michael Field⁹, Lauren Collen⁹, Jonas Bibus⁴, David Illig⁴, Meino Rohlfs⁴, Ziqi Yu⁴, Shaohong Yang¹⁰, Wenjuan Li¹, Craig D Platt¹¹, Phillip H Comella⁵, Daniel Jordan⁵, Mayte Suárez-Fariñas⁵, Mohammed F Alosaimi¹², Lauren A Peters⁵, Jeremie Rosain¹³, Claire Fieschi¹⁴, Anne Puel¹⁵, Elena W Y Hsieh¹⁶, Takeo Naito¹⁷, Zhiyang Zeng¹⁸, Marta Velasco Rodríguez-Belvís¹⁹, Laura Palomino¹⁹, Peter Küster²⁰, Dalin Li¹⁰, Christoph Klein²¹, Scott B Snapper²², Jean-Laurent Casanova²³, Raif Geha¹¹, Edward Hoffenberg²⁴, Dermot P B McGovern¹⁰, Eric Schadt⁵, Daniel Kotlarz²⁵, Dali Li²⁶, Aleixo M Muise²⁷

Affiliations

¹ Cell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
² Cell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama, Japan.
³ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China.
⁴ Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
⁵ Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
⁶ Division of Pediatric Rheumatology, Michigan Medicine, Ann Arbor, Michigan.
⁷ Immunopathology Department, Saint-Louis Hospital, AP-HP, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, and Imagine Institute, Paris Cité University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
⁸ Cell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
⁹ Division of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁰ F. Widjaja Foundation Inflammatory Bowel Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
¹¹ Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
¹² Immunology Research Laboratory, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹³ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, and Imagine Institute, Paris Cité University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York; Study Center for Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.
¹⁴ Immunopathology Department, Saint-Louis Hospital, AP-HP, Paris, France.
¹⁵ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, and Imagine Institute, Paris Cité University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
¹⁶ Division of Allergy and Immunology, Departments of Pediatrics and Internal Medicine, Children's Medical Center Dallas, University of Texas Southwestern, Dallas, Texas; Department of Immunology, University of Texas Southwestern, Dallas, Texas.
¹⁷ Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
¹⁸ Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China.
¹⁹ Sección de Gastroenterología y Nutrición Pediátrica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
²⁰ Department of Paediatrics, Clemens Hospital GmbH Münster, Munster, Nordrhein-Westfalen, Germany.
²¹ Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Munich, Munich, Germany.
²² Division of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts.
²³ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, and Imagine Institute, Paris Cité University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York; Department of Pediatrics, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris, France; Howard Hughes Medical Institute, New York, New York.
²⁴ Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
²⁵ Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University Munich, Munich, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Munich, Munich, Germany; Institute of Translational Genomics, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany. Electronic address: daniel.kotlarz@med.uni-muenchen.de.
²⁶ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China. Electronic address: dlli@bio.ecnu.edu.cn.
²⁷ Cell and Systems Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Pediatrics, Institute of Medical Science, and Biochemistry, University of Toronto, Toronto, Ontario, Canada. Electronic address: aleixo.muise@utoronto.ca.

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.

Keywords: BIRC3; Monogenic IBD; RIPK1; cIAP2.

Abstract

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