Nuclear relocation of normal huntingtin.
In Huntington's Disease (HD), the huntingtin protein (Htt) includes an expanded polyglutamine domain. Since mutant Htt concentrates in the nucleus of affected neurons, we have inquired whether normal Htt (Q16--23) is also able to access the nucleus. We observe that a major pool of normal full-length Htt of HeLa cells is anchored to endosomes and also detect RNase-sensitive nuclear foci which include a 70-kDa N-terminal Htt fragment. Agents which damage DNA trigger caspase-3-dependent cleavage of Htt and dramatically relocate the 70 kDa fragment to the nucleoplasm. Considering that polyglutamine tracts stimulate caspase activation, mutant Htt is therefore poised to enter the nucleus. These considerations help rationalize the nuclear accumulation of Htt which is characteristic of HD and provide a first example of involvement of caspase cleavage in release of membrane-bound proteins which subsequently enter the nucleus.
Tao
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Pathology Department and Cell Biology Program, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
Tartakoff
A M
AM
D021581:Active Transport, Cell Nucleus; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D003902:Detergents / Q000494:pharmacology; D011992:Endosomes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010455:Peptides / Q000378:metabolism; D017434:Protein Structure, Tertiary
D003902:Detergents; D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D020169:Caspases