Abstract
Sox2 is a key transcriptional factor for maintaining pluripotency of stem cells. Sox2 deficiency causes neurodegeneration and impairs neurogenesis. Although the transcriptional regulation of Sox2 has been extensively studied, the mechanisms that control Sox2 protein turnover are yet to be clarified. Here we show that the RING-finger ubiquitin ligase complex CUL4ADET1-COP1 and the deubiquitylase OTUD7B govern Sox2 protein stability during neural progenitor cells (NPCs) differentiation. Sox2 expression declines concordantly with OTUD7B and reciprocally with CUL4A and COP1 levels upon NPCs differentiation. COP1, as the substrate receptor, interacts directly with and ubiquitylates Sox2, while OTUD7B removes polyUb conjugates from Sox2 and increases its stability. COP1 knockdown stabilizes Sox2 and prevents differentiation, while OTUD7B knockdown destabilizes Sox2 and induces differentiation. Thus, CUL4ADET1-COP1 and OTUD7B exert opposite roles in regulating Sox2 protein stability at the post-translational level, which represents a critical regulatory mechanism involved in the maintenance and differentiation of NPCs.
Highlights
The relative abundance and functional modifications of proteins are regulated by a complicated cellular machine, the ubiquitin-proteasome system (UPS) that adds or removes away ubiquitin to or from the target proteins[14]
We show that the Cullin-RING finger ligase (CRL) complex CUL4ADET1-COP1 and the deubiquitylase (DUB) ovarian tumor (OTU) domain-containing protein 7B (OTUD7B)/Cezanne-1 govern Sox[2] protein stability during neural progenitor cells (NPCs) differentiation
The results showed that compared with control, the treatment of MLN4924 promoted NPC maintenance marked by increased Sox[2] level and decreased neuN level, while PR-619 and b-AP-15 enhanced cell differentiation marked by decreased Sox[2] level and increased neuN level (Supplementary Fig. 8c)
Summary
The relative abundance and functional modifications of proteins are regulated by a complicated cellular machine, the ubiquitin-proteasome system (UPS) that adds or removes away ubiquitin to or from the target proteins[14]. The specificity of the reaction is provided by the E3 ligase complex, which conjugates activated ubiquitin to the substrates. The UPS is regulated by a class of deubiquitylating enzymes responsible for removing ubiquitin conjugates from the substrates[14]. We show that the Cullin-RING finger ligase (CRL) complex CUL4ADET1-COP1 and the deubiquitylase (DUB) OTUD7B/Cezanne-1 govern Sox[2] protein stability during NPCs differentiation. Sox[2] expression declines concordantly with OTUD7B and reciprocally with Cullin 4A (CUL4A) and constitutive photomorphogenic 1 (COP1, known as RFWD2) protein levels upon NPCs differentiation. CUL4ADET1-COP1 and OTU domain-containing protein 7B (OTUD7B) play roles in fining tune Sox[2] stability by ubiquitylation or deubiquitylation, which represents a critical regulatory mechanism governing the maintenance and differentiation of NPCs and might be potential targets for the treatment of neural degenerative diseases
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