Herpesvirus-associated ubiquitin-specific protease (HAUSP) modulates peroxisome proliferator-activated receptor γ (PPARγ) stability through its deubiquitinating activity

Kyeong Won Lee, Jin Gu Cho, Chul Min Kim, A. Young Kang, Min Kim, Byung Yong Ahn, Sung Soo Chung, Key Hwan Lim, Kwang Hyun Baek, Jong Hyuk Sung, Kyong Soo Park, Sang Gyu Park

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Abstract

The peroxisome proliferator-activated receptor γ (PPARγ) is a central regulator of adipogenesis and modulates glucose and lipid metabolism. In this study, herpesvirus-associated ubiquitin-specific protease (HAUSP) was isolated as a binding partner of PPARγ. Both endogenous and exogenous PPARγ associated with HAUSP in co-immunoprecipitation analysis. HAUSP, but not the catalytically inactive HAUSP C223S mutant, increased the stability of both endogenous and exogenousPPARγ through its deubiquitinating activity. Site-directed mutagenesis experiments showed that the Lys462 residue of PPARγ is critical for ubiquitination. HBX 41,108, a specific inhibitor of HAUSP, abolished the increase inPPARγ stability induced by HAUSP. In addition, knockdown of endogenous HAUSP using siRNA decreased PPARγ protein levels. HAUSP enhanced the transcriptional activity of both exogenous and endogenous PPARγ in luciferase activity assays. Quantitative RT-PCR analysis showed that HAUSP increased the transcript levels of PPARγ target genes in HepG2 cells, resulting in the enhanced uptake of glucose and fatty acids, and vice versa, upon siRNA knockdown of HAUSP. In vivo analysis using adenoviruses confirmed that HAUSP, but not the HAUSP C223S mutant, decreased blood glucose and triglyceride levels, which are associated with the increased expression of endogenous PPARγ and lipid accumulation in the liver. Our results demonstrate that the stability and activity of PPARγ are modulated by the deubiquitinating activity of HAUSP, which may be a target for the development of anti-diabetic drugs.

Original languageEnglish
Pages (from-to)32886-32896
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number46
DOIs
Publication statusPublished - 2013 Nov 15

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lee, K. W., Cho, J. G., Kim, C. M., Kang, A. Y., Kim, M., Ahn, B. Y., Chung, S. S., Lim, K. H., Baek, K. H., Sung, J. H., Park, K. S., & Park, S. G. (2013). Herpesvirus-associated ubiquitin-specific protease (HAUSP) modulates peroxisome proliferator-activated receptor γ (PPARγ) stability through its deubiquitinating activity. Journal of Biological Chemistry, 288(46), 32886-32896. https://doi.org/10.1074/jbc.M113.496331