Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation
Silva, Joana; Alkan, Ferhat; Ramalho, Sofia; Snieckute, Goda; Prekovic, Stefan; Garcia, Ana Krotenberg; Hernández-Pérez, Santiago; Kammen, Rob van der; Barnum, Danielle; Hoekman, Liesbeth; Altelaar, Maarten; Zwart, Wilbert; Suijkerbuijk, Saskia J E; Bekker-Jensen, Simon; Faller, William James
(2022) Nature Communications, volume 13, issue 1, pp. 1 - 12
(Article)
Abstract
The small intestine is a rapidly proliferating organ that is maintained by a small population of Lgr5-expressing intestinal stem cells (ISCs). However, several Lgr5-negative ISC populations have been identified, and this remarkable plasticity allows the intestine to rapidly respond to both the local environment and to damage. However, the mediators
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of such plasticity are still largely unknown. Using intestinal organoids and mouse models, we show that upon ribosome impairment (driven by Rptor deletion, amino acid starvation, or low dose cyclohexamide treatment) ISCs gain an Lgr5-negative, fetal-like identity. This is accompanied by a rewiring of metabolism. Our findings suggest that the ribosome can act as a sensor of nutrient availability, allowing ISCs to respond to the local nutrient environment. Mechanistically, we show that this phenotype requires the activation of ZAKɑ, which in turn activates YAP, via SRC. Together, our data reveals a central role for ribosome dynamics in intestinal stem cells, and identify the activation of ZAKɑ as a critical mediator of stem cell identity.
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Keywords: Gcn2, Regeneration, Translation, Quantification, Expression, Kinase, Messenger-rna, Identification, Progenitors, Differentiation, General, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We thank Drs. Vivian S. W. Li and Pedro Antas (both Crick Institute, United Kingdom) for generating and sharing the ZAK KO mouse, and Dr. Christoffer Clemmensen and Charlotte Svendsen (both University of Copenhagen, Denmark) for help with dietary interventions in mice. Work in the Faller lab is supported by the KWF (NKI-2016-10535,NKI-2021-13878), and the NWO (OCENW.KLEIN.263). JS is supported by an EMBO Long Term Fellowship [210-2018]. Work in the Bekker-Jensen lab was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 863911 - PHYRIST). S.J.E.S. and A.K.G. were financially supported by the K.W.F. (Young Investigator Grant 11491/2018-1). We would like to acknowledge the NKI- AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support. Funding Information: We thank Drs. Vivian S. W. Li and Pedro Antas (both Crick Institute, United Kingdom) for generating and sharing the ZAK KO mouse, and Dr. Christoffer Clemmensen and Charlotte Svendsen (both University of Copenhagen, Denmark) for help with dietary interventions in mice. Work in the Faller lab is supported by the KWF (NKI-2016-10535,NKI-2021-13878), and the NWO (OCENW.KLEIN.263). JS is supported by an EMBO Long Term Fellowship [210-2018]. Work in the Bekker-Jensen lab was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 863911 - PHYRIST). S.J.E.S. and A.K.G. were financially supported by the K.W.F. (Young Investigator Grant 11491/2018-1). We would like to acknowledge the NKI- AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support. Publisher Copyright: © 2022, The Author(s).
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