Mutant huntingtin: nuclear translocation and cytotoxicity mediated by GAPDH.
The pathophysiology of Huntington's disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.
Bae
Byoung-Il
BI
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hara
Makoto R
MR
Cascio
Matthew B
MB
Wellington
Cheryl L
CL
Hayden
Michael R
MR
Ross
Christopher A
CA
Ha
Hyo Chol
HC
Li
Xiao-Jiang
XJ
Snyder
Solomon H
SH
Sawa
Akira
A
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)