The Ski protein negatively regulates Siah2-mediated HDAC3 degradation.
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.
Zhao
Hong-Ling
HL
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5222, USA.
Ueki
Nobuhide
N
Hayman
Michael J
MJ
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000098563:Seven in Absentia Proteins; D000099186:Histone Deacetylase 3
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D007976:Leupeptins; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D000099186:Histone Deacetylase 3; C060614:SKI protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde