ARTS mediates apoptosis and regeneration of the intestinal stem cell niche

Elle Koren, Yahav Yosefzon, Roi Ankawa, Despina Soteriou, Avi Jacob, Alexander Nevelsky, Rahamim Ben-Yosef, Gil Bar-Sela and Yaron Fuchs ()
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Elle Koren: Technion Israel Institute of Technology
Yahav Yosefzon: Technion Israel Institute of Technology
Roi Ankawa: Technion Israel Institute of Technology
Despina Soteriou: Technion Israel Institute of Technology
Avi Jacob: Bar-Ilan University
Alexander Nevelsky: Rambam Health Care Campus
Rahamim Ben-Yosef: Rambam Health Care Campus
Gil Bar-Sela: Rambam Health Care Campus
Yaron Fuchs: Technion Israel Institute of Technology

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06941-4

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