Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells. Author Yi Xu, Yang Zhang, Juan García-Cañaveras, Lili Guo, Mengyuan Kan, Sixiang Yu, Ian Blair, Joshua Rabinowitz, Xiaolu Yang Publication Year 2020 Type Journal Article Abstract 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. Keywords Animals, Mice, Cell Line, Cell Differentiation, Epigenesis, Genetic, Histones, Ketoglutaric Acids, Embryonic Stem Cells, Chaperone-Mediated Autophagy, Octamer Transcription Factor-3, SOXB1 Transcription Factors Journal Science Volume 369 Issue 6502 Pages 397-403 Date Published 2020 Jul 24 ISSN Number 1095-9203 DOI 10.1126/science.abb4467 Alternate Journal Science PMCID PMC7939502 PMID 32703873 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML