The Ski protein negatively regulates Siah2-mediated HDAC3 degradation

• Published in: Biochemical and biophysical research communications 2010-09, Vol.399 (4), p.623-628
• Main Authors: Zhao, Hong-Ling, Ueki, Nobuhide, Hayman, Michael J.
• Format: Article
• Language: English
• Subjects: Animals; Cercopithecus aethiops; Co-repressor complex; COS Cells; Cysteine Proteinase Inhibitors - pharmacology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzyme Stability; HDAC3; Histone Deacetylases - metabolism; Humans; Immunoprecipitation; Leupeptins - pharmacology; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Proteasomal degradation; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Siah2; Ski; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2010.07.127

► Siah2 is in the same complex with HDAC3 and mediates proteasomal degradation of HDAC3. ► Ski and Siah2 are in the same complex. ► Co-expressed Ski can stabilize Siah2, which is an indication of the inhibition of Siah2 E3 ubiquitin ligase activity. ► Ski stabilizes HDAC3 by being in the same complex with Siah2 and inhibiting Siah2 E3 ubiquitin ligase activity. Ski acts as a transcriptional co-repressor by multiple direct and indirect interactions with several distinct repression complexes. Ski represses retinoic acid (RA) signaling by interacting with, and stabilizing, key components of the co-repressor complex, namely, HDAC3. However, little is known as to how the Ski protein can stabilize HDAC3. In the present study, we identified the Siah2 protein as a potential E3 ubiquitin ligase that mediated proteasomal degradation of HDAC3. Reciprocal co-immunoprecipitation assays further revealed that Ski interacts with Siah2. Furthermore, co-expression of the Ski protein stabilized the level of Siah2 protein. Since Siah2 regulates its own level of expression by self-degradation, the stabilization of Siah2 by Ski is an indication that Ski association leads to inhibition of Siah2 E3 ubiquitin ligase activity. Only wild-type Ski and Ski truncation mutants that were in the same complex with Siah2 could stabilize HDAC3 levels. Taken together, the results suggest that association with Ski leads to inhibition of Siah2 E3 ubiquitin ligase activity and in this way, the Ski protein inhibits Siah2-mediated proteasomal degradation of HDAC3.