title: Suppression of PPARγ through MKRN1-mediated ubiquitination and degradation prevents adipocyte differentiation.
abstract: 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.
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: J-H
authors: JH
authors: Kim
authors: Department of Food Science and Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, Republic of Korea.
authors: K W
authors: KW
authors: Park
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: E-W
authors: EW
authors: Lee
authors: Department of Food Science and Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, Republic of Korea.
authors: W-S
authors: WS
authors: Jang
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: J
authors: J
authors: Seo
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: S
authors: S
authors: Shin
authors: Department of Agrofood Resources, National Academy of Agricultural Science, RDA, Suwon 441-853, Republic of Korea.
authors: K-A
authors: KA
authors: Hwang
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: J
authors: J
authors: Song
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C410808:Makorin ring finger protein 1; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D008239:Lysine