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; Yaron Fuchs

doi:10.1038/s41467-018-06941-4

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, Yaron Fuchs

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

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.

Original language	English
Article number	4582
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06941-4
State	Published - 2 Nov 2018

Bibliographical note

Publisher Copyright:
© 2018, The Author(s).

Funding

We apologize to colleagues whose important contributions we could not cite due to space constraints. We thank I. Maniv, Y. Koren, A. Feldman and R. Sinreich for advice and technical assistance; V. Zlobin at the PCRA for animal health care; X. Velasquez at the Technion Biomedical Core Facility for sample preparations; S. Kirzner for cell sorting and all members of the Fuchs lab. Y.F. is the Deloro Career Advancement Chair and is supported by GIF (I-2381-412.13/2015) and ICRF (15-771-RCDA) grants.

Funders	Funder number
Israel Cancer Research Fund	15-771-RCDA
German-Israeli Foundation for Scientific Research and Development	I-2381-412.13/2015

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title = "ARTS mediates apoptosis and regeneration of the intestinal stem cell niche",

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.",

author = "Elle Koren and Yahav Yosefzon and Roi Ankawa and Despina Soteriou and Avi Jacob and Alexander Nevelsky and Rahamim Ben-Yosef and Gil Bar-Sela and Yaron Fuchs",

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doi = "10.1038/s41467-018-06941-4",

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AU - Yosefzon, Yahav

AU - Ankawa, Roi

AU - Soteriou, Despina

AU - Jacob, Avi

AU - Nevelsky, Alexander

AU - Ben-Yosef, Rahamim

AU - Bar-Sela, Gil

AU - Fuchs, Yaron

PY - 2018/11/2

Y1 - 2018/11/2

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AB - 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.

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ARTS mediates apoptosis and regeneration of the intestinal stem cell niche

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