Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells.

TitleChaperone-mediated autophagy regulates the pluripotency of embryonic stem cells.
Publication TypeJournal Article
Year of Publication2020
AuthorsXu, Y, Zhang, Y, García-Cañaveras, JC, Guo, L, Kan, M, Yu, S, Blair, IA, Rabinowitz, JD, Yang, X
JournalScience
Volume369
Issue6502
Pagination397-403
Date Published2020 07 24
ISSN1095-9203
KeywordsAnimals, Cell Differentiation, Cell Line, Chaperone-Mediated Autophagy, Embryonic Stem Cells, Epigenesis, Genetic, Histones, Ketoglutaric Acids, Mice, Octamer Transcription Factor-3, SOXB1 Transcription Factors
Abstract

<p>Embryonic stem cells can propagate indefinitely in a pluripotent state, able to differentiate into all types of specialized cells when restored to the embryo. What sustains their pluripotency during propagation remains unclear. Here, we show that core pluripotency factors OCT4 and SOX2 suppress chaperone-mediated autophagy (CMA), a selective form of autophagy, until the initiation of differentiation. Low CMA activity promotes embryonic stem cell self-renewal, whereas its up-regulation enhances differentiation. CMA degrades isocitrate dehydrogenases IDH1 and IDH2 and reduces levels of intracellular α-ketoglutarate, an obligatory cofactor for various histone and DNA demethylases involved in pluripotency. These findings suggest that CMA mediates the effect of core pluripotency factors on metabolism, shaping the epigenetic landscape of stem cells and governing the balance between self-renewal and differentiation.</p>

DOI10.1126/science.abb4467
Alternate JournalScience
PubMed ID32703873
Grant ListR01 CA182675 / CA / NCI NIH HHS / United States
R01 CA184867 / CA / NCI NIH HHS / United States
R01 CA235760 / CA / NCI NIH HHS / United States
P30 ES013508 / ES / NIEHS NIH HHS / United States