TY - JOUR
T1 - Chaperone-mediated autophagy sustains haematopoietic stem-cell function
AU - Dong, Shuxian
AU - Wang, Qian
AU - Kao, Yun Ruei
AU - Diaz, Antonio
AU - Tasset, Inmaculada
AU - Kaushik, Susmita
AU - Thiruthuvanathan, Victor
AU - Zintiridou, Aliona
AU - Nieves, Edward
AU - Dzieciatkowska, Monika
AU - Reisz, Julie A.
AU - Gavathiotis, Evripidis
AU - D’Alessandro, Angelo
AU - Will, Britta
AU - Cuervo, Ana Maria
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/3/4
Y1 - 2021/3/4
N2 - The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells1. This process requires major molecular adaptations to allow HSCs to meet the regulatory and metabolic requirements for cell division2–4. The mechanisms that govern cellular reprograming upon stem-cell activation, and the subsequent return of stem cells to quiescence, have not been fully characterized. Here we show that chaperone-mediated autophagy (CMA)5, a selective form of lysosomal protein degradation, is involved in sustaining HSC function in adult mice. CMA is required for protein quality control in stem cells and for the upregulation of fatty acid metabolism upon HSC activation. We find that CMA activity in HSCs decreases with age and show that genetic or pharmacological activation of CMA can restore the functionality of old mouse and human HSCs. Together, our findings provide mechanistic insights into a role for CMA in sustaining quality control, appropriate energetics and overall long-term HSC function. Our work suggests that CMA may be a promising therapeutic target for enhancing HSC function in conditions such as ageing or stem-cell transplantation.
AB - The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells1. This process requires major molecular adaptations to allow HSCs to meet the regulatory and metabolic requirements for cell division2–4. The mechanisms that govern cellular reprograming upon stem-cell activation, and the subsequent return of stem cells to quiescence, have not been fully characterized. Here we show that chaperone-mediated autophagy (CMA)5, a selective form of lysosomal protein degradation, is involved in sustaining HSC function in adult mice. CMA is required for protein quality control in stem cells and for the upregulation of fatty acid metabolism upon HSC activation. We find that CMA activity in HSCs decreases with age and show that genetic or pharmacological activation of CMA can restore the functionality of old mouse and human HSCs. Together, our findings provide mechanistic insights into a role for CMA in sustaining quality control, appropriate energetics and overall long-term HSC function. Our work suggests that CMA may be a promising therapeutic target for enhancing HSC function in conditions such as ageing or stem-cell transplantation.
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U2 - 10.1038/s41586-020-03129-z
DO - 10.1038/s41586-020-03129-z
M3 - Article
C2 - 33442062
AN - SCOPUS:85100004684
SN - 0028-0836
VL - 591
SP - 117
EP - 123
JO - Nature
JF - Nature
IS - 7848
ER -