Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation

Joana Silva, Ferhat Alkan, Sofia Ramalho, Goda Snieckute, Stefan Prekovic, Ana Krotenberg Garcia, Santiago Hernández-Pérez, Rob Kammen, Danielle Barnum, Liesbeth Hoekman, Maarten Altelaar, Wilbert Zwart, Saskia Jacoba Elisabeth Suijkerbuijk, Simon Bekker-Jensen and William James Faller ()
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Joana Silva: The Netherlands Cancer Institute
Ferhat Alkan: The Netherlands Cancer Institute
Sofia Ramalho: The Netherlands Cancer Institute
Goda Snieckute: University of Copenhagen
Stefan Prekovic: The Netherlands Cancer Institute
Ana Krotenberg Garcia: Faculty of Science, Utrecht University
Santiago Hernández-Pérez: The Netherlands Cancer Institute
Rob Kammen: The Netherlands Cancer Institute
Danielle Barnum: The Netherlands Cancer Institute
Liesbeth Hoekman: The Netherlands Cancer Institute
Maarten Altelaar: The Netherlands Cancer Institute
Wilbert Zwart: The Netherlands Cancer Institute
Saskia Jacoba Elisabeth Suijkerbuijk: Faculty of Science, Utrecht University
Simon Bekker-Jensen: University of Copenhagen
William James Faller: The Netherlands Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32220-4

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DOI: 10.1038/s41467-022-32220-4

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