Sanghuh College of Life Sciences, Konkuk University, Seoul, Korea.
Department of Biotechnology, CHA University, Seongnam, Korea.
FASEB J. 2019 Jun;33(6):7707-7720. doi: 10.1096/fj.201802643R. Epub 2019 Mar 21.
Peroxisome proliferator-activated receptor (PPAR)-γ has been implicated as a key player in the regulation of adiponectin levels both transcriptional and posttranscriptional mechanisms. Herein, we show that PPAR-γ interacts with human antigen R (HuR) and that the PPAR-γ-HuR complex dissociates following activation of PPAR-γ by rosiglitazone, a specific ligand of PPAR-γ. This rosiglitazone-dependent dissociation of HuR from PPAR-γ leads to nucleocytoplasmic shuttling of HuR and its binding to the 3'-UTR of adiponectin mRNA. PPAR-γ with H321A and H447A double mutation (PPAR-γ), a mutant lacking ligand-binding activity, impaired HuR dissociation from the PPAR-γ-HuR complex, resulting in reduced nucleocytoplasmic shuttling, even in the presence of rosiglitazone. Consequently, rosiglitazone up-regulated adiponectin levels by modulating the stability of adiponectin mRNA, whereas these effects were abolished by HuR ablation or blocked in cells expressing the PPAR-γ mutant, indicating that the interaction of PPAR-γ and HuR is a critical event during adiponectin expression. Taken together, the findings demonstrate a novel mechanism for regulating adiponectin expression at the posttranscriptional level and suggest that ligand-mediated activation of PPAR-γ to interfere with interaction of HuR could offer a therapeutic strategy for inflammation-associated diseases that involve decreased adiponectin mRNA stability.-Hwang, J. S., Lee, W. J., Hur, J., Lee, H. G., Kim, E., Lee, G. H., Choi, M.-J., Lim, D.-S., Paek, K. S., Seo, H. G. Rosiglitazone-dependent dissociation of HuR from PPAR-γ regulates adiponectin expression at the posttranscriptional level.
过氧化物酶体增殖物激活受体 (PPAR)-γ 被认为是调节脂联素水平的关键因子，包括转录和转录后机制。在此，我们表明 PPAR-γ 与人类抗原 R (HuR) 相互作用，并且 PPAR-γ 被罗格列酮激活后，PPAR-γ-HuR 复合物会解离，罗格列酮是 PPAR-γ 的特异性配体。这种 HuR 从 PPAR-γ 上的解离导致 HuR 的核质穿梭及其与脂联素 mRNA 3'-UTR 的结合。具有 H321A 和 H447A 双突变（PPAR-γ）的 PPAR-γ，一种缺乏配体结合活性的突变体，损害了 HuR 从 PPAR-γ-HuR 复合物中的解离，导致核质穿梭减少，即使存在罗格列酮也是如此。因此，罗格列酮通过调节脂联素 mRNA 的稳定性来上调脂联素水平，而 HuR 缺失或在表达 PPAR-γ 突变体的细胞中阻断这些作用会使这些效应丧失，表明 PPAR-γ 和 HuR 的相互作用是脂联素表达的一个关键事件。综上所述，这些发现表明了一种在转录后水平调节脂联素表达的新机制，并表明配体介导的 PPAR-γ 激活以干扰 HuR 的相互作用可能为涉及脂联素 mRNA 稳定性降低的炎症相关疾病提供一种治疗策略。-Hwang, J. S., Lee, W. J., Hur, J., Lee, H. G., Kim, E., Lee, G. H., Choi, M.-J., Lim, D.-S., Paek, K. S., Seo, H. G. Rosiglitazone-dependent dissociation of HuR from PPAR-γ regulates adiponectin expression at the posttranscriptional level.
