Abstract
PPARγ (Peroxisome proliferator-activated receptor γ) is a nuclear receptor involved in lipid homeostasis and related metabolic diseases. Acting as a transcription factor, PPARγ is a master regulator for adipocyte differentiation. Here, we reveal that CHIP (C-terminus of HSC70-interacting protein) suppresses adipocyte differentiation by functioning as an E3 ligase of PPARγ. CHIP directly binds to and induces ubiquitylation of the PPARγ protein, leading to proteasome-dependent degradation. Stable overexpression or knockdown of CHIP inhibited or promoted adipogenesis, respectively, in 3T3-L1 cells. On the other hand, a CHIP mutant defective in E3 ligase could neither regulate PPARγ protein levels nor suppress adipogenesis, indicating the importance of CHIP-mediated ubiquitylation of PPARγ in adipocyte differentiation. Lastly, a CHIP null embryo fibroblast exhibited augmented adipocyte differentiation with increases in PPARγ and its target protein levels. In conclusion, CHIP acts as an E3 ligase of PPARγ, suppressing PPARγ-mediated adipogenesis.
Highlights
Metabolism[7,8]
We show that stable overexpression of CHIP in 3T3-L1 cells suppresses adipocyte differentiation, while CHIP knockdown promotes adipogenesis
An E3 ligase-defective mutant, H260Q, was able to bind to PPARγ2, while K30A, a mutant defective in the tetratricopeptide repeat (TPR) domain, could not, corroborating the finding that the TPR region is required for the interaction between CHIP and PPARγ2 (Fig. 1h)[40]
Summary
Metabolism[7,8]. While its expression is observed in other tissues, PPARγis predominantly expressed in adipose tissues[9]. CHIP (C-terminus of HSC70-interacting protein) is an E3 ligase with a variety of target proteins, including p53, PTEN (Phosphatase and tensin homolog), Tau, and RIPK3 (Receptor-interacting serine/threonine-protein kinase 3)[32,33,34,35] It contains a U-box domain responsible for ubiquitylation activities and a tetratricopeptide repeat (TPR) domain required for protein interactions. We show that stable overexpression of CHIP in 3T3-L1 cells suppresses adipocyte differentiation, while CHIP knockdown promotes adipogenesis In accordance with these observations, CHIP-null mouse embryonic fibroblasts exhibited increased adipocyte differentiation with elevated levels of PPARγ.
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