Journal Article

Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation

Snieckute, Goda, Zwart, Wilbert, Suijkerbuijk, Saskia Jacoba Elisabeth, Ramalho, Sofia, Hernández-Pérez, Santiago, Altelaar, Maarten, Silva, Joana, Prekovic, Stefan, van der Kammen, Rob, Garcia, Ana Krotenberg, Bekker-Jensen, Simon, Alkan, Ferhat, Faller, William James, Barnum, Danielle, Hoekman, Liesbeth

2022

Overview

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. Intestinal stem cells are responsible for replenishing cells within the high-turnover intestinal epithelium. Here they show that ribosome dynamics affect intestinal stem cell identity through a mechanism that is triggered by changes in nutrient availability.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/100 / 13/106 / 13/95 / 38/1 / 38/88 / 38/89 / 45/91 / 631/337/574/1789 / 631/532/2437 / 631/80/86/2369 / Amino acid starvation / Amino acids / Animal models / Animals / Availability / Cell activation / Epithelium / Fetuses / Humanities and Social Sciences / Impairment / Intestinal Mucosa - metabolism / Intestine / Intestine, Small - metabolism / Intestines / Mice / multidisciplinary / Nutrient availability / Organoids / Phenotypes / Plastic properties / Plasticity / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Ribosomes - metabolism / Science / Science (multidisciplinary) / Small intestine / Stem cell transplantation / Stem cells / Stem Cells - metabolism / Yes-associated protein