Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation
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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; van der Kammen, Rob; Barnum, Danielle; Hoekman, Liesbeth; Altelaar, Maarten; Zwart, Wilbert; Suijkerbuijk, Saskia Jacoba Elisabeth; Bekker-Jensen, Simon; Faller, William James.
I: Nature Communications, Bind 13, Nr. 1, 4492, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation
AU - Silva, Joana
AU - Alkan, Ferhat
AU - Ramalho, Sofia
AU - Snieckute, Goda
AU - Prekovic, Stefan
AU - Garcia, Ana Krotenberg
AU - Hernández-Pérez, Santiago
AU - van der Kammen, Rob
AU - Barnum, Danielle
AU - Hoekman, Liesbeth
AU - Altelaar, Maarten
AU - Zwart, Wilbert
AU - Suijkerbuijk, Saskia Jacoba Elisabeth
AU - Bekker-Jensen, Simon
AU - Faller, William James
N1 - Publisher Copyright: © 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-022-32220-4
DO - 10.1038/s41467-022-32220-4
M3 - Journal article
C2 - 35918345
AN - SCOPUS:85135265594
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4492
ER -
ID: 316679110