Nanog is a master pluripotency factor of embryonic stem cells (ESCs). Stable expression of Nanog is essential to maintain the stemness of ESCs. However, Nanog is a short-lived protein and quickly degraded by the ubiquitin-dependent proteasome system. In previous reports, a number of ubiquitin ligases have been reported to regulate Nanog stability, however, the de-ubiquitinase of Nanog remain elusive.
In a recent study, scientists from East China Normal University, Shanghai Institute of Materia Medica and Tongji University report that the deubiquitinase USP21 interacts with, deubiquitinates and stabilizes Nanog, and therefore maintains the protein level of Nanog in mouse ESCs (mESCs). Loss of USP21 results in Nanog degradation, mESCs differentiation and reduces somatic cell reprogramming efficiency.
USP21 is a transcriptional target of the LIF/STAT3 pathway and is downregulated upon differentiation. Moreover, differentiation cues promote ERK-mediated phosphorylation and dissociation of USP21 from Nanog, thus leading to Nanog degradation. In addition, USP21 is recruited to gene promoters by Nanog to deubiquitinate histone H2A at K119 and thus facilitates Nanog-mediated gene expression. These findings provide a regulatory mechanism by which extrinsic signals regulate mESC fate via deubiquitinating Nanog.
The ubiquitin-dependent proteasome is one of the key systems that regulate cellular protein level, cell function and cell fate. Recent development of general proteasome inhibitors as anti-cancer drugs indicates this system is also important drug targets. The discovery of the new functions of deubiquitinase USP21 in ESCs may lead to deeper understanding of stem cell fate determination, more efficient ways of somatic cell reprogramming, and possibly new therapies targeting cancer stem cells.
This study has been published in Nature Communications (25 Nov 2016, doi:10.1038/ncomms13594).
This study was conceived and supervised by Prof. WANG Ping (Tongji University) and Prof. XIE Xin (Shanghai Institute of Materia Medica, CAS). Ph.D. candidates JIN Jiali (East China Normal University) and LIU Jian (Shanghai Institute of Materia Medica, CAS) contributed equally to this work and shared first authorship.
The current study was supported by grants from the Ministry of Science and Technology of China, Chinese Academy of Sciences, the National Natural Science Foundation of China, and Shanghai Municipal Government.
Link to the article：http://www.nature.com/articles/ncomms13594
USP21 plays an important role in maintaining the self-renewal of mESC by deubiquitinating and stabilizing Nanog. The expression and function of USP21 are regulated by LIF/STAT and FGF signaling pathways. (Image by Nature Communications).
Shanghai Institute of Materia Medica, CAS
(Credit：XIE Xin；Editor：PAN Peihua）