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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
33
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pubmed:dateCreated |
2007-8-16
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pubmed:abstractText |
HIV protease inhibitors (HIV-PIs) target the HIV aspartyl protease, which cleaves the HIV gag-pol polyprotein into shorter proteins required for the production of new virions. HIV-PIs are a cornerstone of treatment for HIV but have been associated with lipodystrophy and other side effects. In both human and mouse fibroblasts, we show that HIV-PIs caused an accumulation of prelamin A. The prelamin A in HIV-PI-treated fibroblasts migrated more rapidly than nonfarnesylated prelamin A, comigrating with the farnesylated form of prelamin A that accumulates in ZMPSTE24-deficient fibroblasts. The accumulation of farnesyl-prelamin A in response to HIV-PI treatment was exaggerated in fibroblasts heterozygous for Zmpste24 deficiency. HIV-PIs inhibited the endoproteolytic processing of a GFP-prelamin A fusion protein. The HIV-PIs did not affect the farnesylation of HDJ-2, nor did they inhibit protein farnesyltransferase in vitro. HIV-PIs also did not inhibit the activities of the isoprenyl-cysteine carboxyl methyltransferase ICMT or the prenylprotein endoprotease RCE1 in vitro, but they did inhibit ZMPSTE24 (IC(50): lopinavir, 18.4 +/- 4.6 microM; tipranavir, 1.2 +/- 0.4 microM). We conclude that the HIV-PIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. The inhibition of ZMPSTE24 by HIV-PIs could play a role in the side effects of these drugs.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-10085069,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-10592860,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-10692417,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-11121396,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-11136544,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-11399759,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-11808750,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-12235369,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-12390557,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-12714972,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-12870540,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-12913070,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-14600514,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-14609943,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-15611058,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-15635112,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-15843403,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-15937076,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-16207929,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-16297189,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-17217329,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-17709742,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-2335559,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-3290900,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-8524103,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-9015299,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-9065405,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17652517-9562584
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0027-8424
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
14
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pubmed:volume |
104
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
13432-7
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
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pubmed:year |
2007
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pubmed:articleTitle |
HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells.
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pubmed:affiliation |
Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. coffinie@ucla.edu
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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