Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells

Yi Xu, Yang Zhang, Juan C. García-Cañaveras, Lili Guo, Mengyuan Kan, Sixiang Yu, Ian A. Blair, Joshua D. Rabinowitz, Xiaolu Yang

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)397-403
Number of pages7
JournalScience
Volume369
Issue number6502
DOIs
StatePublished - Jul 24 2020

All Science Journal Classification (ASJC) codes

  • General

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