Suppression of PPARγ through MKRN1-mediated ubiquitination and degradation prevents adipocyte differentiation

J. H. Kim; K. W. Park; E. W. Lee; W. S. Jang; J. Seo; S. Shin; K. A. Hwang; J. Song

doi:10.1038/cdd.2013.181

Suppression of PPARγ through MKRN1-mediated ubiquitination and degradation prevents adipocyte differentiation

J. H. Kim, K. W. Park, E. W. Lee, W. S. Jang, J. Seo, S. Shin, K. A. Hwang, J. Song

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72 Citations (Scopus)

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.

Original language	English
Pages (from-to)	594-603
Number of pages	10
Journal	Cell Death and Differentiation
Volume	21
Issue number	4
DOIs	https://doi.org/10.1038/cdd.2013.181
Publication status	Published - 2014 Apr

Bibliographical note

Funding 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).

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Molecular Biology
Cell Biology

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10.1038/cdd.2013.181

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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.",

author = "Kim, {J. H.} and Park, {K. W.} and Lee, {E. W.} and Jang, {W. S.} and J. Seo and S. Shin and Hwang, {K. A.} and J. Song",

note = "Funding 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).",

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AU - Park, K. W.

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AU - Seo, J.

AU - Shin, S.

AU - Hwang, K. A.

AU - Song, J.

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N2 - 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.

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Suppression of PPARγ through MKRN1-mediated ubiquitination and degradation prevents adipocyte differentiation

Abstract

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