Snord15b Maintains Stemness of Intestinal Stem Cells via Enhancement of Alternative Splicing of Btrc Short Isoform for Suppression of β‐Catenin Ubiquitination

Abstract Intestinal epithelium is derived from Lgr5 ⁺ intestinal stem cells (ISCs) located at the crypt base. However, how small nucleolar RNAs (snoRNAs) regulate ISC stemness remains elusive. Here, a conserved snoRNA, Snord15b , that is highly expressed in ISCs is identified. Snord15b knockout abolishes the self‐renewal capacity of ISCs and impairs epithelial regeneration. Mechanistically, Snord15b interacts with interleukin enhancer‐binding factor 2 (Ilf2) to recruit splicing factors, which mediates alternative splicing of Btrc to form a short isoform of Btrc, resulting in abrogation of E3 ligase complex formation for ubiquitination of β‐catenin. Subsequently, stable β‐catenin translocates into the nucleus of ISCs for activation of the Wnt/β‐catenin signaling pathway, leading to ISC stemness maintenance and intestinal regeneration. Of note, knockout of Snord15b or Ilf2 increases β‐catenin ubiquitination to suppress activation of Wnt signaling. Furthermore, Btrc knockout blocks β‐catenin ubiquitination to enhance the stemness of ISCs and intestinal regeneration. These findings reveal that Snord15b ‐Ilf2 association mediates alternative splicing of Btrc short isoform to inhibit β‐catenin ubiquitination for ISC stemness maintenance.