Abstract
Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces thisubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitatesthe K63-linked ubiquitination of nuclear p53 and itstransactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples withWT p53 reveal that TRAF6 overexpression negatively correlates with apoptosis and predicts poorresponse to chemotherapy and radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation, and such mechanism may contribute to tumor development and drug resistance.
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