Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling
Toshiaki Teratani, Kengo Tomita, Sachiko Toma-Fukai, Yutaro Nakamura, Toshimasa Itoh, Hikaru Shimizu, Yasunaga Shiraishi, Nao Sugihara, Masaaki Higashiyama, Takahiko Shimizu, Ikuo Inoue, Yasuhiro Takenaka, Ryota Hokari, Takeshi Adachi, Toshiyuki Shimizu, Soichiro Miura, Takanori Kanai∥
Abstract
The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ has been implicated in the pathogenesis of various human diseases including fatty liver. Although nuclear translocation of PPARγ plays an important role in PPARγ signaling, details of the translocation mechanisms have not been elucidated. Here we demonstrate that PPARγ2 translocates to the nucleus and activates signal transduction through H2O2-dependent formation of a PPARγ2 and transportin (Tnpo)1 complex via redox-sensitive disulfide bonds between cysteine (Cys)176 and Cys180 of the former and Cys512 of the latter. Using hepatocyte cultures and mouse models, we show that cytosolic H2O2/Tnpo1-dependent nuclear translocation enhances the amount of DNA-bound PPARγ and downstream signaling, leading to triglyceride accumulation in hepatocytes and liver. These findings expand our understanding of the mechanism underlying the nuclear translocation of PPARγ, and suggest that the PPARγ and Tnpo1 complex and surrounding redox environment are potential therapeutic targets in the treatment of PPARγ-related diseases.