USP8 maintains embryonic stem cell stemness via deubiquitination of EPG5

Haifeng Gu, Xingxing Shi, Chao Liu, Chaoqun Wang, Ning Sui, Yu Zhao, Jiaqi Gong, Fuping Wang, Hong Zhang, Wei Li () and Tongbiao Zhao ()
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Haifeng Gu: Institute of Zoology, Chinese Academy of Sciences
Xingxing Shi: Institute of Zoology, Chinese Academy of Sciences
Chao Liu: Institute of Zoology, Chinese Academy of Sciences
Chaoqun Wang: Institute of Zoology, Chinese Academy of Sciences
Ning Sui: Institute of Zoology, Chinese Academy of Sciences
Yu Zhao: Institute of Zoology, Chinese Academy of Sciences
Jiaqi Gong: Institute of Zoology, Chinese Academy of Sciences
Fuping Wang: Institute of Zoology, Chinese Academy of Sciences
Hong Zhang: University of Chinese Academy of Sciences
Wei Li: Institute of Zoology, Chinese Academy of Sciences
Tongbiao Zhao: Institute of Zoology, Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract Embryonic stem cells (ESCs) can propagate in an undifferentiated state indefinitely in culture and retain the potential to differentiate into any somatic lineage as well as germ cells. The catabolic process autophagy has been reported to be involved in ESC identity regulation, but the underlying mechanism is still largely unknown. Here we show that EPG5, a eukaryotic-specific autophagy regulator which mediates autophagosome/lysosome fusion, is highly expressed in ESCs and contributes to ESC identity maintenance. We identify that the deubiquitinating enzyme USP8 binds to the Coiled-coil domain of EPG5. Mechanistically, USP8 directly removes non-classical K63-linked ubiquitin chains from EPG5 at Lysine 252, leading to enhanced interaction between EPG5 and LC3. We propose that deubiquitination of EPG5 by USP8 guards the autophagic flux in ESCs to maintain their stemness. This work uncovers a novel crosstalk pathway between ubiquitination and autophagy through USP8-EPG5 interaction to regulate the stemness of ESCs.

Date: 2019
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DOI: 10.1038/s41467-019-09430-4

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