Acetylation of sox2 induces its nuclear export in embryonic stem cells.
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.
Baltus
Gretchen A
GA
Developmental and Molecular Pathways, Novartis Institute of Biomedical Research,Cambridge, Massachusetts 02139, USA.
Kowalski
Michael P
MP
Zhai
Huili
H
Tutter
Antonin V
AV
Quinn
Douglas
D
Wall
Daniel
D
Kadam
Shilpa
S
D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D002853:Chromatography, Liquid; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D050880:p300-CBP Transcription Factors