Stub1 maintains proteostasis of master transcription factors in embryonic stem cells.

Md Mahfuz Al Mamun, Muhammad Riaz Khan, Yifu Zhu, Yuwei Zhang, Shuai Zhou, Ran Xu, Ihtisham Bukhari, Rick F Thorne, Jinming Li, Xu Dong Zhang, Guangzhi Liu, Song Chen, Mian Wu, Xiaoyuan Song

Cell reports 2022 Jun 07

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The pluripotency and differentiation states of embryonic stem cells (ESCs) are regulated by a set of core transcription factors, primarily Sox2, Oct4, and Nanog. Although their transcriptional regulation has been studied extensively, the contribution of posttranslational modifications in Sox2, Oct4, and Nanog are poorly understood. Here, using a CRISPR-Cas9 knockout library screen in murine ESCs, we identify the E3 ubiquitin ligase Stub1 as a negative regulator of pluripotency. Manipulation of Stub1 expression in murine ESCs shows that ectopic Stub1 expression significantly reduces the protein half-life of Sox2, Oct4, and Nanog. Mechanistic investigations reveal Stub1 catalyzes the polyubiquitination and 26S proteasomal degradation of Sox2 and Nanog through K48-linked ubiquitin chains and Oct4 via K63 linkage. Stub1 deficiency positively enhances somatic cell reprogramming and delays differentiation, whereas its enforced expression triggers ESC differentiation. The discovery of Stub1 as an integral pluripotency regulator strengthens our understanding of ESC regulation beyond conventional transcriptional control mechanisms. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Md Mahfuz Al Mamun, Muhammad Riaz Khan, Yifu Zhu, Yuwei Zhang, Shuai Zhou, Ran Xu, Ihtisham Bukhari, Rick F Thorne, Jinming Li, Xu Dong Zhang, Guangzhi Liu, Song Chen, Mian Wu, Xiaoyuan Song. Stub1 maintains proteostasis of master transcription factors in embryonic stem cells. Cell reports. 2022 Jun 07;39(10):110919