Valosin-containing protein (VCP) in novel feedback machinery between abnormal protein accumulation and transcriptional suppression.
Abnormal protein accumulation is often observed in human neurodegenerative disorders such as polyglutamine diseases and Parkinson disease. Genetic and biochemical analyses indicate that valosin-containing protein (VCP) is a crucial molecule in the pathogenesis of human neurodegenerative disorders. We report here that VCP was specifically modified in neuronal cells with abnormal protein accumulation; this modification caused the translocation of VCP into the nucleus. Modification-mimic forms of VCP induced transcriptional suppression with deacetylation of core histones, leading to cell atrophy and the decrease of de novo protein synthesis. Preventing VCP nuclear translocation in polyglutamine-expressing neuronal cells and Drosophila eyes mitigated neurite retraction and eye degenerations, respectively, concomitant with the recovery of core histone acetylation. This represents a novel feedback mechanism that regulates abnormal protein levels in the cytoplasm during physiological processes, as well as in pathological conditions such as abnormal protein accumulation in neurodegenerations.
Koike
Masaaki
M
Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies & Solution Oriented Research for Science and Technology, Kyoto 606-8501, Japan.
Fukushi
Junpei
J
Ichinohe
Yuzuru
Y
Higashimae
Naoki
N
Fujishiro
Masahiko
M
Sasaki
Chiyomi
C
Yamaguchi
Masahiro
M
Uchihara
Toshiki
T
Yagishita
Saburo
S
Ohizumi
Hiroshi
H
Hori
Seiji
S
Kakizuka
Akira
A
D021581:Active Transport, Cell Nucleus; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D004331:Drosophila melanogaster / Q000235:genetics; D005822:Genetic Vectors; D006657:Histones / Q000737:chemistry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D006657:Histones; D010455:Peptides; C097188:polyglutamine; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; C000614180:Vcp protein, rat
J Biol Chem. 1998 Nov 27;273(48):32353-9
9822716
J Struct Biol. 2004 Apr-May;146(1-2):32-43
15037235
Biochim Biophys Acta. 2008 Jul;1783(7):1418-35
18284922
Cytogenet Genome Res. 2003;100(1-4):261-75
14526188
J Neuropathol Exp Neurol. 2006 Jun;65(6):571-81
16783167
Neurosci Lett. 2003 Jun 5;343(2):77-80
12759168
Nature. 1995 Nov 23;378(6555):403-6
7477379
Genes Dev. 2002 Jun 1;16(11):1345-55
12050113
J Biol Chem. 2004 Dec 3;279(49):51376-85
15456787
Nature. 2001 Oct 18;413(6857):739-43
11607033
Genes Cells. 2009 Apr;14(4):483-97
19335618
Biochim Biophys Acta. 2008 Dec;1782(12):744-8
18845250
Neurology. 2005 Oct 25;65(8):1304-5
16247064
J Neurosci. 2007 May 23;27(21):5535-45
17522299
Hum Mol Genet. 2010 Jan 15;19(2):235-49
19843543
Cell Death Differ. 2006 Apr;13(4):539-50
16167067
Hum Mol Genet. 2002 Apr 15;11(8):905-14
11971872
Biochem Soc Trans. 2008 Feb;36(Pt 1):105-8
18208395
J Biol Chem. 2008 Oct 31;283(44):30289-99
18715868
Mol Cell Biochem. 2006 Aug;288(1-2):47-57
16583140
Hum Mol Genet. 2006 Oct 15;15(20):3012-23
16959795
Cancer Res. 2005 Sep 1;65(17):7533-40
16140914
Nat Genet. 2000 Sep;26(1):29-36
10973244
Science. 2001 Mar 23;291(5512):2423-8
11264541
J Clin Invest. 2002 Nov;110(10):1389-98
12438434
Trends Genet. 1998 Oct;14(10):396-402
9820028
Cell Death Differ. 2002 Mar;9(3):264-73
11859409
Nat Genet. 2004 Apr;36(4):377-81
15034582
EMBO J. 2003 Dec 15;22(24):6537-49
14657026
Science. 2001 May 25;292(5521):1552-5
11375494
Genes Cells. 1999 Dec;4(12):743-56
10620019
Genes Cells. 2007 Jul;12(7):889-901
17584300
Annu Rev Biochem. 2006;75:243-69
16756492
Hum Mol Genet. 2003 Sep 15;12(18):2301-9
12915485
J Biol Chem. 2002 Dec 6;277(49):47358-65
12351637
Nat Genet. 1996 Jun;13(2):196-202
8640226
Cell Death Differ. 2001 Oct;8(10):977-84
11598795
Trends Cell Biol. 2004 Dec;14(12):703-11
15564047
Hum Mol Genet. 2003 Jan 1;12(1):1-12
12490527
Trends Biochem Sci. 2002 Dec;27(12):619-27
12468231
J Biol Chem. 2005 Dec 16;280(50):41332-41
16234241
J Biol Chem. 2005 Sep 9;280(36):31870-81
16027165
J Biol Chem. 2002 Aug 16;277(33):29496-502
12039950
Trends Cell Biol. 1998 Jun;8(6):245-9
9695849
Mol Cell. 2004 Jul 2;15(1):95-105
15225551
Curr Top Dev Biol. 2008;85:83-113
19147003
Curr Opin Chem Biol. 1997 Oct;1(3):300-8
9667866
Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
17565364
Muscle Nerve. 2009 Mar;39(3):389-91
19208399
Science. 2006 Oct 6;314(5796):130-3
17023659