Differential effect of HDAC3 on cytoplasmic and nuclear huntingtin aggregates.
Histone deacetylases (HDACs) are potential therapeutic targets of polyglutamine (pQ) diseases including Huntington's disease (HD) that may function to correct aberrant transcriptional deactivation caused by mutant pQ proteins. HDAC3 is a unique class 1 HDAC found in both the cytoplasm and in the nucleus. However, the precise functions of HDAC3 in the two cellular compartments are only vaguely known. HDAC3 directly binds to huntingtin (Htt) with short pQ and this interaction is important for suppressing neurotoxicity induced by HDAC3. With long pQ Htt, the interaction with HDAC3 is inhibited, and this supposedly promotes neuronal death, indicating that HDAC3 would be a good therapeutic target for HD. However, the knockout of one HDAC3 allele did not show any efficacy in reducing neurodegenerative symptoms in a mouse model of HD. Therefore, the role of HDAC3 in the pathogenesis of HD has yet to be fully elucidated. We attempted to resolve this issue by focusing on the different roles of HDAC3 on cytoplasmic and nuclear Htt aggregates. In addition to supporting the previous findings, we found that HDAC3 preferentially binds to nuclear Htt over cytoplasmic ones. Specific HDAC3 inhibitors increased the total amount of Htt aggregates by increasing the amount of nuclear aggregates. Both cytoplasmic and nuclear Htt aggregates were able to suppress endogenous HDAC3 activity, which led to decreased nuclear proteasome activity. Therefore, we concluded that Htt aggregates impair nuclear proteasome activity through the inhibition of HDAC3. Our findings provide new insights regarding cross-compartment proteasome regulation.
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Tatsuo
T
Mano
Department of Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Saitama, Japan.
Takayoshi
T
Suzuki
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Shoji
S
Tsuji
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Saitama, Japan.
Atsushi
A
Iwata
D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013379:Substrate Specificity; D000099186:Histone Deacetylase 3
D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex; D066329:Protein Aggregates; D000099186:Histone Deacetylase 3; C086055:HTT protein, human