Human Molecular Genetics Advance Access published online on December 1, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi426
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Neurology - Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110; Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110
* To whom correspondence should be addressed. Mutations in the AAA + protein (ATPase associated with a variety of cellular activities) p97/VCP (valosin-containing protein) cause a dominantly inherited syndrome of inclusion body myopathy, Paget's disease of the bone and fronto-temporal dementia (IBMPFD). p97/VCP is a ubiquitously expressed protein that participates in a number of cellular processes including endoplasmic reticulum associated degradation (ERAD). p97/VCP aids in the extraction of ubiquitinated proteins from the endoplasmic reticulum (ER) and facilitates their delivery to the proteasome. This study focuses on the effects of disease associated p97/VCP mutations on this pathway. We show that p97/VCP containing the most prevalent IBMPFD-associated mutation, R155H, has normal ATPase activity and hexameric structure. However, when expressed in cultured cells, both this and a second IBMPFD-associated p97/VCP mutant increase the overall level of ubiquitin-conjugated proteins and specifically impair degradation of mutant
Received September 24, 2005
Accepted November 12, 2005
Article
Inclusion body myopathy associated mutations in p97/VCP impair endoplasmic reticulum associated degradation
Conrad C. Weihl 1 *,
Seema Dalal 2,
Alan Pestronk 3,
and
Phyllis I. Hanson 2
2 Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110
3 Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110
Conrad C. Weihl, E-mail: weihlc{at}neuro.wustl.edu
Abstract 
F508-CFTR handled by the ERAD pathway. These effects are similar to those previously described for an ATPase deficient p97/VCP mutant and suggest that IBMPFD mutations impair p97/VCP cellular function. In a subset of cells, IBMPFD mutations also promote formation of aggregates that contain p97/VCP, ubiquitin-conjugates and ER resident proteins. Undegraded mutant F508-CFTR also accumulates in these aggregates. We conclude that IBMPFD mutations in p97/VCP disrupt ERAD and that this may contribute to the pathogenesis of IBMPFD.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Halawani, A. C. LeBlanc, I. Rouiller, S. W. Michnick, M. J. Servant, and M. Latterich Hereditary Inclusion Body Myopathy-Linked p97/VCP Mutations in the NH2 Domain and the D1 Ring Modulate p97/VCP ATPase Activity and D2 Ring Conformation Mol. Cell. Biol., August 15, 2009; 29(16): 4484 - 4494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A Greenberg How citation distortions create unfounded authority: analysis of a citation network BMJ, July 23, 2009; 339(jul20_3): b2680 - b2680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Gitcho, J. Strider, D. Carter, L. Taylor-Reinwald, M. S. Forman, A. M. Goate, and N. J. Cairns VCP Mutations Causing Frontotemporal Lobar Degeneration Disrupt Localization of TDP-43 and Induce Cell Death J. Biol. Chem., May 1, 2009; 284(18): 12384 - 12398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Ju, S. E. Miller, P. I. Hanson, and C. C. Weihl Impaired Protein Aggregate Handling and Clearance Underlie the Pathogenesis of p97/VCP-associated Disease J. Biol. Chem., October 31, 2008; 283(44): 30289 - 30299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C C Weihl, P Temiz, S E Miller, G Watts, C Smith, M Forman, P I Hanson, V Kimonis, and A Pestronk TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia J. Neurol. Neurosurg. Psychiatry, October 1, 2008; 79(10): 1186 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Hebert and M. Molinari In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases Physiol Rev, October 1, 2007; 87(4): 1377 - 1408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Isaacson, V. E. Pye, P. Simpson, H. H. Meyer, X. Zhang, P. S. Freemont, and S. Matthews Detailed Structural Insights into the p97-Npl4-Ufd1 Interface J. Biol. Chem., July 20, 2007; 282(29): 21361 - 21369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Weihl, S. E. Miller, P. I. Hanson, and A. Pestronk Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice Hum. Mol. Genet., April 15, 2007; 16(8): 919 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Heubes and O. Stemmann The AAA-ATPase p97-Ufd1-Npl4 is required for ERAD but not for spindle disassembly in Xenopus egg extracts J. Cell Sci., April 15, 2007; 120(8): 1325 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Helfrich, J. C. Crockett, L. J. Hocking, and F. P. Coxon The Pathogenesis of Osteoclast Diseases: Some Knowns, but Still Many Unknowns IBMS BoneKEy, February 1, 2007; 4(2): 61 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. U. Hubbers, C. S. Clemen, K. Kesper, A. Boddrich, A. Hofmann, O. Kamarainen, K. Tolksdorf, M. Stumpf, J. Reichelt, U. Roth, et al. Pathological consequences of VCP mutations on human striated muscle Brain, February 1, 2007; 130(2): 381 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Talbot and O. Ansorge Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R182 - R187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Allen, A. Buchberger, and M. Bycroft The PUB Domain Functions as a p97 Binding Module in Human Peptide N-Glycanase J. Biol. Chem., September 1, 2006; 281(35): 25502 - 25508. [Abstract] [Full Text] [PDF]
|
|