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 ..