HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-08, Vol.104 (33), p.13432-13437
• Main Authors: Coffinier, Catherine, Hudon, Sarah E, Farber, Emily A, Chang, Sandy Y, Hrycyna, Christine A, Young, Stephen G, Fong, Loren G
• Format: Article
• Language: English
• Subjects: Accumulation; All terrain vehicles; Antibodies; Base Sequence; Biological Sciences; Cell lines; Cells; DNA Primers; Enzymes; Fibroblasts; HEK293 cells; Highly active antiretroviral therapy; HIV; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Humans; Lamin Type A; Lamins; Membrane Proteins - antagonists & inhibitors; Metalloendopeptidases - antagonists & inhibitors; Methylation; Nuclear Proteins - metabolism; Protease inhibitors; Protein Precursors - metabolism; Proteinase inhibitors; Proteins; Side effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0704212104

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 (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.