The Ubiquitin Ligase SIAH2 Negatively Regulates Glucocorticoid Receptor Activity and Abundance

Abstract

Glucocorticoids are clinically essential drugs used routinely to control inflammation. However, a host of metabolic side effects manifests upon usage beyond a few days. In the present study, we tested the hypothesis that seven-in-absentia mammalian homolog-2 (SIAH2), a ubiquitin ligase that regulates adipogenesis, is important for controlling adipocyte size, inflammation, and the ability of adipose tissue to expand in response to a glucocorticoid challenge. Using mice with global deletion of SIAH2 exposed or not to corticosterone, we found that adipocytes are larger in response to glucocorticoids in the absence of SIAH2. In addition, SIAH2 regulates glucocorticoid receptor (GR) transcriptional activity and total GR protein abundance. Moreover, these studies reveal that there is an increased expression of genes involved in fibrosis and inflammatory signaling pathways found in white adipose tissue in response to glucocorticoids in the absence of SIAH2. In summary, this is the first study to identify a role for SIAH2 to regulate transcriptional activity and abundance of the GR, which leads to alterations in adipose tissue size and gene expression during in vivo exposure to glucocorticoids.

Acquired Glucocorticoid Resistance Due to Homologous Glucocorticoid Receptor Downregulation: A Modern Look at an Age-Old Problem

“…Lastly, a recent study by Burke et al [141] identified the E3 ligase, seven-in-absentiamammalian homolog-2 (Siah2) as a modulator of GRα protein levels. Siah2 is a known regulator of fat mass and inflammation within adipose tissue [159,160] and has been shown to lead to the agonist-dependent activation of steroid receptors, such as GRα [156].…”