HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells
HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells
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DOI：
10.1073/pnas.0704212104
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发表时间：
2007-08-14
影响因子：
11.1
通讯作者：
Fong, Loren G.
中科院分区：
文献类型：
--
作者：
Coffinier, Catherine;Hudon, Sarah E.;Fong, Loren G.
HIV蛋白酶抑制剂（HIV-PI）靶向HIV乙酰基蛋白酶，该蛋白酶将HIV gag-pol多聚蛋白切割成产生新病毒体所需的较短蛋白质。HIV-PI是治疗HIV的基石，但与脂肪代谢障碍和其他副作用有关。在人类和小鼠成纤维细胞中，我们发现HIV-1感染引起了前层蛋白A的积累。HIV-PI处理的成纤维细胞中的前核纤层蛋白A比非法尼基化的前核纤层蛋白A迁移更快，与在ZMPSTE 24缺陷的成纤维细胞中积累的法尼基化形式的前核纤层蛋白A共迁移。在Zmpste 24缺陷杂合子成纤维细胞中，响应于HIV-PI治疗的法尼基-前核层蛋白A的积累被夸大。HIV-PI抑制GFP-前层蛋白A融合蛋白的内切蛋白水解加工。体外实验表明，HIV-PI不影响HDJ-2的法尼基化，也不抑制蛋白法尼基转移酶。在体外，HIV-PI也不抑制异戊二烯基-半胱氨酸羧基甲基转移酶ICMT或异戊二烯基蛋白内切蛋白酶RCE 1的活性，但它们确实抑制ZMPSTE 24（IC 50：洛匹那韦，18.4 +/- 4.6 μ M;替拉那韦，1.2 +/- 0.4 μ M）。我们得出结论，HIV-PI抑制ZMPSTE 24，导致法尼基-前核纤层蛋白A的积累。HIV-PI对ZMPSTE 24的抑制可能在这些药物的副作用中起作用。
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 mu M; tipranavir, 1.2 +/- 0.4 mu M). 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.