ARTS mediates apoptosis and regeneration of the intestinal stem cell niche

Nat Commun. 2018 Nov 2;9(1):4582. doi: 10.1038/s41467-018-06941-4.

Abstract

Stem cells (SCs) play a pivotal role in fueling homeostasis and regeneration. While much focus has been given to self-renewal and differentiation pathways regulating SC fate, little is known regarding the specific mechanisms utilized for their elimination. Here, we report that the pro-apoptotic protein ARTS (a Septin4 isoform) is highly expressed in cells comprising the intestinal SC niche and that its deletion protects Lgr5+ and Paneth cells from undergoing apoptotic cell death. As a result, the Sept4/ARTS-/- crypt displays augmented proliferation and, in culture, generates massive cystic-like organoids due to enhanced Wnt/β-catenin signaling. Importantly, Sept4/ARTS-/- mice exhibit resistance against intestinal damage in a manner dependent upon Lgr5+ SCs. Finally, we show that ARTS interacts with XIAP in intestinal crypt cells and that deletion of XIAP can abrogate Sept4/ARTS-/--dependent phenotypes. Our results indicate that intestinal SCs utilize specific apoptotic proteins for their elimination, representing a unique target for regenerative medicine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Proliferation
  • Cytoprotection
  • Gene Deletion
  • Intestines / cytology*
  • Mice, Inbred C57BL
  • Regeneration*
  • Septins / metabolism*
  • Stem Cell Niche*
  • Wnt Signaling Pathway
  • Wounds and Injuries / pathology
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • X-Linked Inhibitor of Apoptosis Protein
  • Sept4 protein, mouse
  • Septins