Acetylation directs survivin nuclear localization to repress STAT3 oncogenic activity.
The multiple functions of the oncofetal protein survivin are dependent on its selective expression patterns within immunochemically distinct subcellular pools. The mechanism by which survivin localizes to these compartments, however, is only partly understood. Here we show that nuclear accumulation of survivin is promoted by CREB-binding protein (CBP)-dependent acetylation on lysine 129 (129K, Lys-129). We demonstrate a mechanism by which survivin acetylation at this position results in its homodimerization, while deacetylation promotes the formation of survivin monomers that heterodimerize with CRM1 and facilitate its nuclear export. Using proteomic analysis, we identified the oncogenic transcription factor STAT3 as a binding partner of nuclear survivin. We show that acetylated survivin binds to the N-terminal transcriptional activation domain of the STAT3 dimer and represses STAT3 transactivation of target gene promoters. Using multiplex PCR and DNA sequencing, we identified a single-nucleotide polymorphism (A → G) at Lys-129 that exists as a homozygous mutation in a neuroblastoma cell line and corresponds with a defect in survivin nuclear localization. Our results demonstrate that the dynamic equilibrium between survivin acetylation and deacetylation at amino acid 129 determines its interaction with CRM1, its subsequent subcellular localization, and its ability to inhibit STAT3 transactivation, providing a potential route for therapeutic intervention in STAT3-dependent tumors.
Wang
Haijuan
H
Department of Pediatrics, Brown University and Rhode Island Hospital, Providence, Rhode Island 02903, USA.
Holloway
Michael P
MP
Ma
Li
L
Cooper
Zachary A
ZA
Riolo
Matthew
M
Samkari
Ayman
A
Elenitoba-Johnson
Kojo S J
KS
Chin
Y Eugene
YE
Altura
Rachel A
RA
D000107:Acetylation; D021581:Active Transport, Cell Nucleus; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D055503:Protein Multimerization; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D015533:Transcriptional Activation; D000097606:Exportin 1 Protein
D050882:CREB-Binding Protein; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins; D008239:Lysine; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D000077022:Survivin; D000097606:Exportin 1 Protein; C107489:BIRC5 protein, human
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