Critical Role for Antiapoptotic Bcl-xL and Mcl-1 in Human Macrophage Survival and Cellular IAP1/2 (cIAP1/2) in Resistance to HIV-Vpr-induced Apoptosis
Critical Role for Antiapoptotic Bcl-xL and Mcl-1 in Human Macrophage Survival and Cellular IAP1/2 (cIAP1/2) in Resistance to HIV-Vpr-induced Apoptosis
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DOI：
10.1074/jbc.m111.312660
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发表时间：
2012-04-27
影响因子：
4.8
通讯作者：
Kumar, Ashok
中科院分区：
文献类型：
--
作者：
Busca, Aurelia;Saxena, Mansi;Kumar, Ashok
巨噬细胞抵抗HIV细胞病变效应，这有助于病毒的持久性和水库的形成。HIV病毒蛋白R （Vpr）是一种有效的原代单核细胞凋亡诱导剂。由于在hiv感染患者的血清和脑脊液中发现了具有生物活性的Vpr，因此我们研究了Vpr对单核细胞源性巨噬细胞和12-肉豆酸13-乙酸酯活化的THP1巨噬细胞的凋亡作用。我们的研究结果表明，原代单核细胞和THP1细胞在分化为巨噬细胞后对vpr诱导的凋亡产生抗性。为了确定Vpr对抗凋亡蛋白表达的影响，我们发现与未分化细胞相比，Vpr没有下调巨噬细胞中抗凋亡抑制剂（IAPs）和Bcl2家族成员的表达，这表明它们参与了对Vpr诱导的凋亡的抵抗。然而，敲低Bcl-xL和Mcl-1蛋白可诱导自发凋亡，对vpr诱导的细胞凋亡易感性无影响。相反，通过sirna和SMAC（第二种线粒体来源的caspases激活剂）下调细胞IAP1 （cIAP1）和cIAP2可使巨噬细胞对vpr诱导的凋亡模拟增敏。总之，我们的研究结果表明，对vpr诱导的细胞凋亡的抗性是由独立于Bcl-xL和Mcl-1的cIAP1/2基因特异性介导的，这些基因在维持细胞活力方面起着关键作用。此外，IAP调节可能是消除巨噬细胞中HIV持久性的潜在策略。
Macrophages are resistant to HIV cytopathic effects, which contributes to viral persistence and reservoir formation. HIV viral protein R (Vpr) is a potent apoptosis-inducing agent for primary monocytes. Because the biologically active Vpr is found in serum and cerebrospinal fluid of HIV-infected patients, we investigated the apoptotic effect of Vpr on monocyte-derived macrophages and phorbol 12-myristate 13-acetate-activated THP1 macrophages. Our results show that primary monocytes and THP1 cells develop resistance to Vpr-induced apoptosis following differentiation into macrophages. To determine the effect of Vpr on the expression of antiapoptotic proteins, we show that in contrast to the undifferentiated cells, Vpr did not down-regulate the expression of antiapoptotic inhibitors of apoptosis (IAPs) and Bcl2 family members in macrophages, suggesting their involvement in resistance to Vpr-induced apoptosis. However, knocking down Bcl-xL and Mcl-1 proteins induced spontaneous apoptosis with no impact on susceptibility to Vpr-induced apoptosis. In contrast, down-regulation of cellular IAP1 (cIAP1) and cIAP2 by using siRNAs and SMAC (second mitochondria-derived activator of caspases) mimetic sensitized macrophages to Vpr-induced apoptosis. Overall, our results suggest that resistance to Vpr-induced apoptosis is specifically mediated by cIAP1/2 genes independent of Bcl-xL and Mcl-1, which play a key role in maintaining cell viability. Moreover, IAP modulation may be a potential strategy to eliminate HIV persistence in macrophages.