Valosin-containing protein gene mutations: cellular phenotypes relevant to neurodegeneration.
Previously, we identified valosin-containing protein (VCP) as a mediator of ER stress-induced cell death. Mutations in the VCP gene including R93, R155, and R191 have been described that manifest clinically as hereditary inclusion body myopathy with Paget's disease of bone and frontotemporal dementia. In addition, other studies have demonstrated that as a consequence of a mutation generated in the second ATP binding domain of VCP (K524A), cells accumulated large cytoplasmic vacuoles and underwent programmed cell death. In order to better understand the biochemical and molecular consequences of the clinically relevant VCP mutations as well as the genetically engineered ATPase-inactive mutant K524A and any relationship these may have to ER stress-induced cell death, we introduced analogous mutations separately and together into the human VCP gene and evaluated their effect on proteasome activity, Huntingtin protein aggregation and ER stress-induced cell death. Our results indicate that the VCP K524A mutant and the triple mutant VCP R93C-R155C-K524A block protein degradation, trigger Huntingtin aggregate formation, and render cells highly susceptible to ER stress-induced cell death as compared to VCPWT or other VCP mutants.
The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
Karen S
KS
Poksay
David T
DT
Madden
Anna K
AK
Peter
Kayvan
K
Niazi
Surita
S
Banwait
Danielle
D
Crippen
Dale E
DE
Bredesen
Rammohan V
RV
Rao
D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019284:Thapsigargin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D025801:Ubiquitin; D019284:Thapsigargin; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
Trends Cell Biol. 2002 May;12(5):212
12062162
EMBO J. 1992 Oct;11(10):3533-40
1382975
Mol Cell Biol. 2009 Aug;29(16):4484-94
19506019
Trends Neurosci. 2003 Aug;26(8):407-10
12900170
Cell Death Differ. 2006 Mar;13(3):385-92
16397584
J Chem Neuroanat. 2004 Sep;28(1-2):67-78
15363492
Hum Mol Genet. 2007 Apr 15;16(8):919-28
17329348
J Cell Biol. 1994 Aug;126(4):945-54
8051214
Nature. 1993 Sep 30;365(6445):459-62
8413590
J Cell Biol. 2000 Jul 10;150(1):F13-9
10893253
Acta Neuropathol. 2007 Jul;114(1):81-94
17569064
Cell Death Differ. 2004 Apr;11(4):372-80
14765132
Hum Mol Genet. 2010 May 1;19(9):1741-55
20147319
J Biol Chem. 2004 Jan 2;279(1):177-87
14561754
Biochim Biophys Acta. 2008 Dec;1782(12):744-8
18845250
Curr Opin Cell Biol. 2004 Dec;16(6):653-62
15530777
Neurochem Res. 2002 Sep;27(9):891-8
12396099
Methods Enzymol. 2005;399:481-90
16338377
J Biol Chem. 2003 Feb 7;278(6):3648-55
12446676
J Biol Chem. 2008 Oct 31;283(44):30289-99
18715868
Cell Death Differ. 2002 Mar;9(3):264-73
11859409
Autophagy. 2010 Feb;6(2):217-27
20104022
Hum Mol Genet. 2006 Aug 15;15(16):2409-20
16822850
EMBO J. 2006 Apr 5;25(7):1547-58
16525503
Neuroreport. 2003 Mar 24;14(4):565-8
12657886
Neuromolecular Med. 2003;4(1-2):21-36
14528050
J Biol Chem. 2006 May 19;281(20):14307-13
16551632
Nat Genet. 2004 Apr;36(4):377-81
15034582
Nature. 2006 Oct 19;443(7113):796-802
17051206
FEBS J. 2007 Feb;274(3):630-58
17288551
Science. 2001 May 25;292(5521):1552-5
11375494
Mol Cell Biol. 2003 Sep;23(18):6469-83
12944474
Neuromuscul Disord. 2009 May;19(5):308-15
19380227
J Biol Chem. 2006 Aug 18;281(33):23686-97
16782707
J Clin Invest. 2005 Oct;115(10):2656-64
16200199
Ann Neurol. 2005 Mar;57(3):457-61
15732117
J Biol Chem. 2003 Aug 29;278(35):32784-93
12807884
Trends Cell Biol. 2000 Dec;10(12):524-30
11121744
Cell Death Differ. 2006 Mar;13(3):415-25
16195741
J Cell Mol Med. 2008 Dec;12(6A):2511-8
18798739
J Cell Biol. 2009 Dec 14;187(6):875-88
20008565
J Biol Chem. 2002 Dec 6;277(49):47358-65
12351637
J Biol Chem. 2009 May 1;284(18):12384-98
19237541
Hum Mol Genet. 2006 Jan 15;15(2):189-99
16321991
Mol Cancer Res. 2006 Sep;4(9):667-81
16966435
FEBS Lett. 2002 Mar 13;514(2-3):122-8
11943137
Cell Death Differ. 2001 Oct;8(10):977-84
11598795
PLoS One. 2010 Jan 26;5(1):e8905
20126661
Brain. 2007 Feb;130(Pt 2):381-93
16984901
Neurology. 2006 Aug 22;67(4):644-51
16790606
J Biol Chem. 2001 Sep 7;276(36):33869-74
11448953
J Biol Chem. 1998 Feb 6;273(6):3562-73
9452483
Eur J Neurosci. 2007 Dec;26(11):3126-40
18005063
Cell Death Differ. 2007 Jun;14(6):1172-80
17396132
J Neuropathol Exp Neurol. 2006 Jun;65(6):571-81
16783167
Nat Cell Biol. 2001 Aug;3(8):740-4
11483959
Neuromuscul Disord. 2009 Nov;19(11):766-72
19828315
Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9
16432136
Genes Cells. 2010 Aug;15(8):911-22
20604808