Linked Life Data

17141218

Source:http://linkedlifedata.com/resource/pubmed/id/17141218

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2007-2-6
pubmed:abstractText
E3 ubiquitin ligases catalyze the conjugation of ubiquitin onto proteins, which acts as a signal for targeting proteins for degradation by the proteasome. Hrd1 is an endoplasmic reticulum (ER) membrane-spanning E3 with its catalytic active RING finger facing the cytosol. We speculated that this topology might allow Hrd1 to ubiquitinate misfolded proteins in the cytosol. We tested this idea by using polyglutamine (polyQ)-containing huntingtin (htt) protein as a model substrate. We found that the protein levels of Hrd1 were increased in cells overexpressing the N-terminal fragment of htt containig an expanded polyQ tract (httN). Forced expression of Hrd1 enhanced the degradation of httN in a RING finger-dependent manner, whereas silencing of endogenous Hrd1 expression by RNA interference stabilized httN. Degradation of httN was found to be p97/VCP-dependent, but independent of Ufd1 and Npl4, all of which are thought to form a complex with Hrd1 during ER-associated degradation. Consistent with its role as an E3 for httN, we demonstrate that Hrd1 interacts with and ubiquitinates httN. Subcellular fractionation and confocal microscopy revealed that Hrd1recruits HttN to the ER and co-localizes with juxtanuclear aggregates of httN in cells. Interaction of Hrd1 with httN was found to be independent of the length of the polyglutamine tract. However, httN with expanded polyglutamine tracts appeared to be a preferred substrate for Hrd1. Functionally, we found that Hrd1 protects cells against the httN-induced cell death. These results suggest that Hrd1 is a novel htt-interacting protein that can target pathogenic httN for degradation and is able to protect cells against httN-induced cell death.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphatases, http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD3, http://linkedlifedata.com/resource/pubmed/chemical/CD3delta antigen, http://linkedlifedata.com/resource/pubmed/chemical/CDC48 protein, http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins, http://linkedlifedata.com/resource/pubmed/chemical/HD protein, human, http://linkedlifedata.com/resource/pubmed/chemical/NPLOC4 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Peptides, http://linkedlifedata.com/resource/pubmed/chemical/Proteins, http://linkedlifedata.com/resource/pubmed/chemical/SYVN1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/UFD1L protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin, http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin-Protein Ligases, http://linkedlifedata.com/resource/pubmed/chemical/polyglutamine
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0014-4827
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
313
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
538-50
pubmed:dateRevised
2010-4-1
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin.
pubmed:affiliation
Medical Biotechnology Center, University of Maryland Biotechnology Institute, 725 W. Lombard Street, Baltimore, MD 21201, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural