The E3 ubiquitin ligase TRIM23 regulates adipocyte differentiation via stabilization of the adipogenic activator PPARγ

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Abstract

Adipocyte differentiation is a strictly controlled process regulated by a series of transcriptional activators. Adipogenic signals activate early adipogenic activators and facilitate the transient formation of early enhanceosomes at target genes. These enhancer regions are subsequently inherited by late enhanceosomes. PPARγ is one of the late adipogenic activators and is known as a master regulator of adipogenesis. However, the factors that regulate PPARγ expression remain to be elucidated. Here, we show that a novel ubiquitin E3 ligase, tripartite motif protein 23 (TRIM23), stabilizes PPARγ protein and mediates atypical polyubiquitin conjugation. TRIM23 knockdown caused a marked decrease in PPARγ protein abundance during preadipocyte differentiation, resulting in a severe defect in late adipogenic differentiation, whereas it did not affect the formation of early enhanceosomes. Our results suggest that TRIM23 plays a critical role in the switching from early to late adipogenic enhanceosomes by stabilizing PPARγ protein possibly via atypical polyubiquitin conjugation.

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Masashi Watanabe

Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Competing interests
The authors declare that no competing interests exist.
Hidehisa Takahashi

Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Competing interests
The authors declare that no competing interests exist.
Yasushi Saeki

Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Takashi Ozaki

Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Competing interests
The authors declare that no competing interests exist.
Shihori Itoh

Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Competing interests
The authors declare that no competing interests exist.
Masanobu Suzuki

Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Competing interests
The authors declare that no competing interests exist.
Wataru Mizushima

Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Competing interests
The authors declare that no competing interests exist.
Keiji Tanaka

Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Shigetsugu Hatakeyama

Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan

For correspondence
hatas@med.hokudai.ac.jp

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: Animal experimentation: All animal protocols were reviewed and approved by the Animal Welfare Committee of Hokkaido University. The work presented in this study is covered by the Animal Protocol Numbers APN-10-0077 and APN13-0040. All researchers, who performed procedures using live animal, were pre-approved by the Animal Welfare Committee of Hokkaido University, based on their completion of required animal use and care training, and acceptable previous experience in animal experiments.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.