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Monoubiquitination is a principal mechanism driving nuclear translocation of Phosphatase and Tensin Homolog Deleted on Chromosome TEN (PTEN). In this study, we describe a novel mechanism wherein Carboxy terminus of Hsc70 Interacting Protein (CHIP) mediates PTEN monoubiquitination, leading to its nuclear import. Western blot analysis revealed a rise in both nuclear and total cellular PTEN levels under monoubiquitination-promoting conditions, an effect that was abrogated by silencing CHIP expression. We established a time-point kinetics of CHIP-mediated nuclear translocation of PTEN using immunocytochemistry and identified a role of Karyopherin α1 (KPNA1) in facilitating nuclear transport of monoubiquitinated PTEN. We further established a direct interaction between CHIP and PTEN inside the nucleus, with CHIP participating in either polyubiquitination or monoubiquitination of nuclear PTEN. Finally, we showed that oxidative stress enhanced CHIP-mediated nuclear import of PTEN, which resulted in increased apoptosis, and decreased cell viability and proliferation, whereas CHIP knockdown counteracted these effects. To the best of our knowledge, this is the first report elucidating CHIP's non-canonical roles on PTEN, which we establish here as a nuclear interacting partner of CHIP.
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