Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells – Science Magazine

Autophagy regulates stemness

Embryonic stem cells can propagate indefinitely and differentiate when called to do so. Xu et al. now analyze how cellular metabolism affects the balance between pluripotency and differentiation (see the Perspective by Borsa and Simon). For cells in the pluripotent state, the transcription factors Oct4 and Sox2 suppress chaperone-mediated autophagy (CMA). When CMA is released with differentiation, the isocitrate dehydrogenases IDH1 and IDH2 are degraded, resulting in less α-ketoglutarate, which is needed by the histone and DNA demethylases that sustain pluripotency. CMA thus links cellular metabolism to epigenetic regulation, tipping the balance between pluripotent renewal and differentiation.

Science, this issue p. 397; see also p. 373

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.