HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells
Copyright policy )HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells
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 forZmpste24deficiency. 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 farnesyltransferasein vitro. HIV-PIs also did not inhibit the activities of the isoprenyl-cysteine carboxyl methyltransferase ICMT or the prenylprotein endoprotease RCE1in vitro, but they did inhibit ZMPSTE24 (IC50: lopinavir, 18.4 ± 4.6 μM; tipranavir, 1.2 ± 0.4 μM). 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.
- Purdue University West Lafayette United States
- University of California, Los Angeles United States
Base Sequence, Humans, Membrane Proteins, Metalloendopeptidases, Nuclear Proteins, HIV Protease Inhibitors, Protein Precursors, Lamin Type A, DNA Primers
Base Sequence, Humans, Membrane Proteins, Metalloendopeptidases, Nuclear Proteins, HIV Protease Inhibitors, Protein Precursors, Lamin Type A, DNA Primers
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