Acetylation of Sox2 Induces its Nuclear Export in Embryonic Stem Cells

Abstract

Embryonic stem (ES) cells require a coordinated network of transcription factors to maintain pluripotency or trigger lineage specific differentiation. Central to these processes are the proteins Oct4, Nanog, and Sox2. Although the transcriptional targets of these factors have been extensively studied, very little is known about how the proteins themselves are regulated, especially at the post-translational level. Post-translational modifications are well documented to have broad effects on protein stability, activity, and cellular distribution. Here, we identify a key lysine residue in the nuclear export signal of Sox2 that is acetylated, and demonstrate that blocking acetylation at this site retains Sox2 in the nucleus and sustains expression of its target genes under hyperacetylation or differentiation conditions. Mimicking acetylation at this site promotes association of Sox2 with the nuclear export machinery. In addition, increased cellular acetylation leads to reduction in Sox2 levels by ubiquitination and proteasomal degradation, thus abrogating its ability to drive transcription of its target genes. Acetylation-mediated nuclear export may be a commonly used regulatory mechanism for many Sox family members, as this lysine is conserved across species and in orthologous proteins. STEM CELLS

Acetylation reduces SOX 9 nuclear entry and ACAN gene transactivation in human chondrocytes

“…(2009) established that murine SOX2 is acetylated by P300/CBP on lysine 75, and enhanced acetylation renders its proteasomal degradation and impairs its capacity to bind its nuclear target. Moreover, this study shows that the K75 site was located in the nuclear export sequence of SOX2 and was speculated to prevent SOX2 from entering the nucleus, further contributing to its instability (Baltus et al ., 2009). SRY, another SOX family member, was found to possess enhanced nuclear localization via interacting with importin β upon acetylation (Thevenet et al ., 2004).…”

Ube2s regulates Sox2 stability and mouse ES cell maintenance

“…These modifications influence its subcellular distribution, protein stability or DNA-binding activity, and subsequently remodel its transcriptional activity towards downstream target genes. [51][52][53] For instance, AKT1 mediates Sox2 phosphorylation at its T118 residue, resulting in increased Sox2 stability and thus ensuring its high protein level in ES cells. 52 On the contrary, acetyltransferase p300 is capable of acetylating Sox2, which is provided as a nuclear export signal and destines Sox2 for ubiquitination and degradation.…”

“…52 On the contrary, acetyltransferase p300 is capable of acetylating Sox2, which is provided as a nuclear export signal and destines Sox2 for ubiquitination and degradation. 51 Obviously, these studies documented regulation of Sox2 stability by ubiquitination; however, the delicate mechanisms mediating this process remain to be illustrated. Interestingly, in this study we detected a robust direct association between E2 Ube2s and Sox2 substrate.…”

Serine 111 Phosphorylation Regulates OCT4A Protein Subcellular Distribution and Degradation

“…Increasing data indicate that the activity of iPS factors is regulated through post-translational modifications. For example, phosphorylation of human SOX2 at Ser-249, Ser-250, and Ser-251 results in the inhibition of SOX2 DNA-binding activity (11), whereas acetylation of mouse SOX2 at Lys-75 by p300/CBP (cAMP-responsive element-binding proteinbinding protein) family proteins enhances nuclear export and degradation of SOX2 through a ubiquitin-mediated degradation pathway (12). Additionally, phosphorylation of human OCT4 at Ser-229 by protein kinase A might partially regulate OCT4 transactivation activity (13).…”