XIAP Deficiency Impairs Colonic Tuft Cell Development and Predisposes to Crohn's Disease

Abstract

A substantial proportion of patients with X‑-linked inhibitor of apoptosis (XIAP) deficiency develop severe and treatment‑-refractory Crohn's disease (CD). Although hematopoietic stem cell transplantation (HSCT) remains the only curative option for these patients, its outcomes are suboptimal, with a long‑-term survival rate of only 50%. Therefore, identifying novel therapeutic targets is crucial to bridge this unmet clinical need. Here, we demonstrate that the abundance of tuft cells is reduced in both XIAP-deficient CD patients and Xiap knockout (Xiap^−/−) mice. Mechanistically, XIAP deficiency reduces TLE4 ubiquitination, resulting in elevated TLE4 protein levels and consequent suppression of Wnt/β‑-catenin–ASCL2 signaling, which is critical for secretory lineage differentiation. Tuft cell deficiency may increase susceptibility to microbial dysregulation, thereby promoting intestinal inflammation. Furthermore, we demonstrate that JAK inhibition promotes tuft cell regeneration and ameliorates mucosal inflammation in Xiap^−/− mice. Consistently, in an XIAP‑-deficient CD patient, treatment with a selective JAK1 inhibitor effectively increased tuft cell proportion and alleviated colonic symptoms. In conclusion, our study identifies tuft cell deficiency as a trigger of intestinal pathology in XIAP‑-deficient Crohn's disease and suggests JAK inhibition as a promising therapeutic strategy.

Keywords

Crohn's disease / JAK inhibition / tuft cell / Wnt/β‑catenin–ASCL2 / XIAP deficiency

References

[1] R. Okumura and K. Takeda, “Roles of Intestinal Epithelial Cells in the Maintenance of Gut Homeostasis,” Experimental & Molecular Medicine 49, no. 5 (2017): e338.

[2] T. Pelaseyed, J. H. Bergstrom, J. K. Gustafsson, et al., “The Mucus and Mucins of the Goblet Cells and Enterocytes Provide the First Defense Line of the Gastrointestinal Tract and Interact With the Immune System,” Immunol Rev 260, no. 1 (2014): 8–20.

[3] J. K. Gustafsson and M. E. V. Johansson, “The Role of Goblet Cells and Mucus in Intestinal Homeostasis,” Nat Rev Gastroenterol Hepatol 19, no. 12 (2022): 785–803.

[4] C. L. Bevins and N. H. Salzman, “Paneth Cells, Antimicrobial Peptides and Maintenance of Intestinal Homeostasis,” Nature Reviews Microbiology 9, no. 5 (2011): 356–368.

[5] C. Schneider, C. E. O'Leary, and R. M. Locksley, “Regulation of Immune Responses by Tuft Cells,” Nat Rev Immunol 19, no. 9 (2019): 584–593.

[6] J. W. McGinty, H. A. Ting, T. E. Billipp, et al., “Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-Helminth Immunity in the Small Intestine but Are Dispensable for Anti-Protist Immunity,” Immunity 52, no. 3 (2020): 528–541e7.

[7] J. von Moltke, M. Ji, H. E. Liang, and R. M. Locksley, “Tuft-Cell-Derived IL-25 Regulates an Intestinal ILC2-epithelial Response Circuit,” Nature 529, no. 7585 (2016): 221–225.

[8] M. A. McGuckin, R. Eri, L. A. Simms, T. H. Florin, and G. Radford-Smith, “Intestinal Barrier Dysfunction in Inflammatory Bowel Diseases,” Inflammatory Bowel Diseases 15, no. 1 (2009): 100–113.

[9] K. Kurokawa, Y. Hayakawa, and K. Koike, “Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals,” International Journal of Molecular Sciences 22, no. 1 (2020): 357.

[10] D. L. Daniels and W. I. Weis, “Beta-catenin Directly Displaces Groucho/TLE Repressors From Tcf/Lef in Wnt-Mediated Transcription Activation,” Nature structural & molecular biology 12, no. 4 (2005): 364–371.

[11] J. E. Flack, J. Mieszczanek, N. Novcic, and M. Bienz, “Wnt-Dependent Inactivation of the Groucho/TLE Co-repressor by the HECT E3 Ubiquitin Ligase Hyd/UBR5,” Molecular Cell 67, no. 2 (2017): 181–193 e5.

[12] A. J. Hanson, H. A. Wallace, T. J. Freeman, R. D. Beauchamp, L. A. Lee, and E. Lee, “XIAP Monoubiquitylates Groucho/TLE to Promote Canonical Wnt signaling,” Molecular cell 45, no. 5 (2012): 619–628.

[13] S. Rigaud, M. C. Fondaneche, N. Lambert, et al., “XIAP Deficiency in Humans Causes an X-linked Lymphoproliferative Syndrome,” Nature 444, no. 7115 (2006): 110–114.

[14] A. C. A. Mudde, C. Booth, and R. A. Marsh, “Evolution of Our Understanding of XIAP Deficiency,” Front Pediatr 9 (2021): 660520.

[15] S. Latour and C. Aguilar, “XIAP Deficiency Syndrome in Humans,” Seminars in Cell & Developmental Biology 39 (2015): 115–123.

[16] R. A. Marsh, K. Rao, P. Satwani, et al., “Allogeneic Hematopoietic Cell Transplantation for XIAP Deficiency: An International Survey Reveals Poor Outcomes,” Blood 121, no. 6 (Feb 7 2013): 877–883.

[17] T. Goncharov, S. Hedayati, M. M. Mulvihill, et al., “Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inflammatory Signaling,” Mol Cell 69, no. 4 (2018): 551–565 e7.

[18] S. A. Hughes, M. Lin, A. Weir, et al., “Caspase-8-driven Apoptotic and Pyroptotic Crosstalk Causes Cell Death and IL-1beta Release in X-Linked Inhibitor of Apoptosis (XIAP) Deficiency,” EMBO J 42, no. 5 (2023): e110468.

[19] J. E. Vince, W. W. Wong, I. Gentle, et al., “Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation,” Immunity 36, no. 2 (2012): 215–227.

[20] M. Yabal, N. Muller, H. Adler, et al., “XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation,” Cell Rep 7, no. 6 (2014): 1796–1808.

[21] K. E. Lawlor, N. Khan, A. Mildenhall, et al., “RIPK3 promotes Cell Death and NLRP3 Inflammasome Activation in the Absence of MLKL,” Nat Commun 6 (2015): 6282.

[22] S. A. Hughes, M. Lin, A. Weir, et al., “Caspase-8-driven Apoptotic and Pyroptotic Crosstalk Causes Cell Death and IL-1beta Release in X-linked Inhibitor of Apoptosis (XIAP) Deficiency,” Embo Journal 42, no. 5 (2023): e110468.

[23] K. E. Lawlor, R. Feltham, M. Yabal, et al., “XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1beta Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation,” Cell reports 20, no. 3 (2017): 668–682.

[24] A. Strigli, S. Gopalakrishnan, Y. Zeissig, et al., “Deficiency in X-linked Inhibitor of Apoptosis Protein Promotes Susceptibility to Microbial Triggers of Intestinal Inflammation,” Science Immunology 6, no. 65 (2021): eabf7473.

[25] A. Wahida, M. Muller, A. Hiergeist, et al., “XIAP Restrains TNF-driven Intestinal Inflammation and Dysbiosis by Promoting Innate Immune Responses of Paneth and Dendritic Cells,” Science Immunology 6, no. 65 (2021): eabf7235.

[26] B. Huang, Z. Chen, L. Geng, et al., “Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways,” Cell 179, no. 5 (2019): 1160–1176.e24.

[27] M. R. Howitt, S. Lavoie, M. Michaud, et al., “Tuft Cells, Taste-chemosensory Cells, Orchestrate Parasite Type 2 Immunity in the Gut,” Science 351, no. 6279 (2016): 1329–1333.

[28] A. Banerjee, C. A. Herring, B. Chen, et al., “Succinate Produced by Intestinal Microbes Promotes Specification of Tuft Cells to Suppress Ileal Inflammation,” Gastroenterology 159, no. 6 (2020): 2101–2115 e5.

[29] Z. Xiong, X. Zhu, J. Geng, et al., “Intestinal Tuft-2 Cells Exert Antimicrobial Immunity via Sensing Bacterial Metabolite N-undecanoylglycine,” Immunity 55, no. 4 (12 2022): 686–700 e7.

[30] M. R. Howitt, S. Lavoie, M. Michaud, et al., “Tuft Cells, Taste-chemosensory Cells, Orchestrate Parasite Type 2 Immunity in the Gut,” Science 351, no. 6279 (2016): 1329–1333.

[31] E. T. McKinley, Y. Sui, Y. Al-Kofahi, et al., “Optimized Multiplex Immunofluorescence Single-Cell Analysis Reveals Tuft Cell Heterogeneity,” JCI Insight 2, no. 11 (2017): e93487.

[32] J. Schuijers, J. P. Junker, M. Mokry, et al., “Ascl2 acts as an R-Spondin/Wnt-Responsive Switch to Control Stemness in Intestinal Crypts,” Cell Stem Cell 16, no. 2 (2015): 158–170.

[33] K. S. Yan, O. Gevaert, G. X. Y. Zheng, et al., “Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity,” Cell Stem Cell 21, no. 1 (2017): 78–90 e6.

[34] G. L. Grice and J. A. Nathan, “The Recognition of Ubiquitinated Proteins by the Proteasome,” Cellular and Molecular Life Sciences 73, no. 18 (2016): 3497–3506.

[35] S. Khanna and L. E. Raffals, “The Microbiome in Crohn's Disease: Role in Pathogenesis and Role of Microbiome Replacement Therapies,” Gastroenterol Clin North Am 46, no. 3 (2017): 481–492.

[36] A. V. Rao, S. S. Ghare, V. Gautam, et al., “Sex Differences in Beneficial and Pathogenic Bacteria in People with HIV (PWH) With a History of Heavy Alcohol Drinking,” Frontiers in Microbiology 16 (2025): 1632949.

[37] G. H. van Muijlwijk, G. van Mierlo, P. Jansen, et al., “Identification of Allobaculum Mucolyticum as a Novel human Intestinal Mucin Degrader,” Gut Microbes 13, no. 1 (2021): 1966278.

[38] L. Chen, Z. Ye, J. Li, et al., “Gut Bacteria Prevotellaceae Related Lithocholic Acid Metabolism Promotes Colonic Inflammation,” Journal of Translational Medicine 23, no. 1 (2025): 55.

[39] C. Argmann, R. Hou, R. C. Ungaro, et al., “Biopsy and Blood-based Molecular Biomarker of Inflammation in IBD,” Gut 72, no. 7 (2023): 1271–1287.

[40] F. Gerbe, E. Sidot, D. J. Smyth, et al., “Intestinal Epithelial Tuft Cells Initiate Type 2 Mucosal Immunity to Helminth Parasites,” Nature 529, no. 7585 (2016): 226–230.

[41] C. Schneider, C. E. O'Leary, and J. von Moltke, “A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling,” Cell 174, no. 2 (2018): 271–284.e14.

[42] Z. Ma, Z. Wang, J. Cao, Y. Dong, and Y. Chen, “Regulatory Roles of Intestinal CD4+ T Cells in Inflammation and Their Modulation by the Intestinal Microbiota,” Gut Microbes 17, no. 1 (2025): 2560019.

[43] M. S. Strine, E. Fagerberg, P. W. Darcy, et al., “Intestinal Tuft Cell Immune Privilege Enables norovirus Persistence,” Sci Immunol 9, no. 93 (2024): eadi7038.

[44] D. Kontoyiannis, M. Pasparakis, T. T. Pizarro, F. Cominelli, and G. Kollias, “Impaired On/off Regulation of TNF Biosynthesis in Mice Lacking TNF AU-rich Elements: Implications for Joint and Gut-associated Immunopathologies,” Immunity 10, no. 3 (1999): 387–398.

[45] F. Gerbe, E. Sidot, D. J. Smyth, et al., “Intestinal Epithelial Tuft Cells Initiate Type 2 Mucosal Immunity to Helminth Parasites,” Nature 529, no. 7585 (2016): 226–230.

[46] X. S. Wu, X. Y. He, J. J. Ipsaro, et al., “OCA-T1 and OCA-T2 Are Coactivators of POU2F3 in the Tuft Cell Lineage,” Nature 607, no. 7917 (Jul 2022): 169–175.

[47] M. Zhao, K. Ren, X. Xiong, et al., “Epithelial STAT6 O-GlcNAcylation Drives a Concerted Anti-Helminth Alarmin Response Dependent on Tuft Cell Hyperplasia and Gasdermin C,” Immunity 55, no. 7 (2022): 1327.

[48] L. G. van der Flier, M. E. van Gijn, P. Hatzis, et al., “Transcription Factor Achaete Scute-Like 2 Controls Intestinal Stem Cell Fate,” 136, no. 5 (Mar 6 2009): 903–912.

[49] E. Batlle, J. T. Henderson, H. Beghtel, et al., “Beta-Catenin and TCF Mediate Cell Positioning in the Intestinal Epithelium by Controlling the Expression of EphB/ephrinB,” Cell 111, no. 2 (2002): 251–263.

[50] P. Bastide, C. Darido, J. Pannequin, et al., “Sox9 regulates Cell Proliferation and Is Required for Paneth Cell Differentiation in the Intestinal Epithelium,” The Journal of Cell Biology 178, no. 4 (2007): 635–648.

[51] Y. Mori-Akiyama, M. van den Born, and J. H. van Es, “SOX9 Is Required for the Differentiation of Paneth Cells in the Intestinal Epithelium,” Gastroenterology 133, no. 2 (2007): 539–546.

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