The central regulator of adipogenesis, PPARγ, is a nuclear receptor that is linked to obesity and metabolic diseases. Here we report that MKRN1 is an E3 ligase of PPARγ that induces its ubiquitination, followed by proteasome-dependent degradation. Furthermore, we identified two lysine sites at 184 and 185 that appear to be targeted for ubiquitination by MKRN1. Stable overexpression of MKRN1 reduced PPARγ protein levels and suppressed adipocyte differentiation in 3T3-L1 and C3H10T1/2 cells. In contrast, MKRN1 depletion stimulated adipocyte differentiation in these cells. Finally, MKRN1 knockout MEFs showed an increased capacity for adipocyte differentiation compared with wild-type MEFs, with a concomitant increase of PPARγ and adipogenic markers. Together, these data indicate that MKRN1 is an elusive PPARγ E3 ligase that targets PPARγ for proteasomal degradation by ubiquitin-dependent pathways, and further depict MKRN1 as a novel target for diseases involving PPARγ.
Bibliographical noteFunding Information:
Acknowledgements. We thank No-Joon Song and Sung-Pil Choi for their help with cell culture and adipocyte differentiation, and Dr. Peter Tontonoz (University of California at Los Angeles) for helpful discussion. This research was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (2010-0017787), and by the Cooperative Research Program for Agricultural Science & Technology Development (2012-PJ008462).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology