CHIP promotes autophagy-mediated degradation of aggregating mutant p53 in hypoxic conditions

Tumor suppressor protein p53 aggregates in the hypoxic core of solid tumors. C terminus of Hsc70-interacting protein (CHIP) displays chaperone as well as E3 ligase activities in both stabilizing and degrading wild-type and mutant p53. In this study, we have discovered that CHIP selectively degrades aggregating mutant p53 under both normal and hypoxic conditions. Silencing of CHIP alleviates degradation of aggregating mutant p53 in both normoxia and hypoxia, but has no significant effect on the level of nonaggregating mutant p53. Although both U-box and TPR domains of CHIP are responsible for p53 degradation, the U-box domain selectively binds to aggregating mutant p53, whereas the TPR domain interacts with nonaggregating mutant p53. The degradation of mutant p53 by CHIP is shown to be via autophagy through K63-linked polyubiquitination. Both in normoxia and under physiological hypoxia, the level of aggregating mutant p53 in the presence of CHIP was reduced threefold, whereas under serum starvation, it was reduced fivefold. Interestingly, both wild-type and mutant p53 interact with and stabilize CHIP at the post-translational level, suggesting a chaperone synergy between p53 and CHIP. This finding may have strong therapeutic significance via selective degradation of oncogenic mutant p53 in regressing hypoxic tumors.