Linked Life Data

20731376

Source:http://linkedlifedata.com/resource/pubmed/id/20731376

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
38
pubmed:dateCreated
2010-9-21
pubmed:abstractText
HIV-1 infection and antiretroviral therapy are associated with a dyslipidemia marked by low levels of high-density lipoprotein and increased cardiovascular disease, but it is unclear whether virion replication plays a causative role in these changes. The HIV-1 Nef protein can impair ATP cassette binding transporter A1 (ABCA1) cholesterol efflux from macrophages, a potentially pro-atherosclerotic effect. This viral inhibition of efflux was correlated with a direct interaction between ABCA1 and Nef. Here, we defined the ABCA1 domain required for the Nef-ABCA1 protein-protein interaction and determined whether this interaction mediates the ability of Nef to downregulate ABCA1. Nef expressed in HEK 293 cells strongly inhibited ABCA1 efflux and protein levels but did not alter levels of cMIR, another transmembrane protein. Analysis of a panel of ABCA1 C-terminal mutants showed Nef binding required the ABCA1 C-terminal amino acids between positions 2225 and 2231. However, the binding of Nef to ABCA1 was not required for inhibition because the C-terminal ABCA1 mutants that did not bind Nef were still downregulated by Nef. Given this discordance, the mechanism of downregulation was investigated and was found to involve the acceleration of ABCA1 protein degradation but did not to depend upon the ABCA1 PEST sequence, which mediates the calpain proteolysis of ABCA1. Furthermore, it did not associate with a Nef-dependent induction of signaling through the unfolded protein response but was significantly dependent upon proteasomal function and could act on an ABCA1 mutant that fails to exit the endoplasmic reticulum. In summary, we show that Nef downregulates ABCA1 function by a post-translational mechanism that stimulates ABCA1 degradation but does not require the ability of Nef to bind ABCA1.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1520-4995
pubmed:author
pubmed:issnType
Electronic
pubmed:day
28
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8338-49
pubmed:dateRevised
2011-9-30
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Mutation of the ATP cassette binding transporter A1 (ABCA1) C-terminus disrupts HIV-1 Nef binding but does not block the Nef enhancement of ABCA1 protein degradation.
pubmed:affiliation
Lipid Metabolism Unit, Center for Computational and Integrative Biology, Richard B. Simches Research Center, Massachusetts General Hospital, 185 Cambridge Street, 7th Floor #7150, Boston, Massachusetts 02114, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural