Cystatin B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-β-treated human macrophages.
Cystatin B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-β-treated human macrophages.
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胱抑素 B 和 HIV 调节 HIV 感染和 INF-β 处理的人类巨噬细胞中的 STAT-1 信号通路。
DOI：
10.1007/s13365-016-0443-6
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发表时间：
2016
影响因子：
3.2
通讯作者：
Meléndez,LM
中科院分区：
文献类型：
--
作者：
Rivera,LE;Kraiselburd,E;Meléndez,LM
半胱氨酸蛋白酶抑制剂B是一种半胱氨酸蛋白酶抑制剂，可诱导HIV在单核细胞衍生的巨噬细胞（MDM）中复制。该蛋白与信号转导和转录激活因子（STAT-1）相互作用，并通过阻止STAT-1易位至细胞核来抑制Vero细胞中的干扰素（IFN-β）反应。半胱氨酸蛋白酶抑制剂B还降低酪氨酸磷酸化STAT-1（STAT-1 PY）的水平。然而，半胱氨酸蛋白酶抑制剂B调节STAT-1磷酸化在MDM中的机制尚不清楚。我们假设半胱氨酸蛋白酶抑制剂B通过抑制STAT-1磷酸化抑制IFN-β抗病毒反应并诱导巨噬细胞储库中的HIV复制。在干扰素-β处理之前用半胱氨酸蛋白酶抑制剂B siRNA转染巨噬细胞或用HIV-ADA感染巨噬细胞，以使用免疫荧光和邻近连接测定来确定半胱氨酸蛋白酶抑制剂B调节在STAT-1定位和活化中的作用。半胱氨酸蛋白酶抑制剂B减少STAT-1 PY及其向细胞核的转运，而HIV感染将未磷酸化的STAT（USTAT-1）保留在细胞核中，避免其退出细胞质进行最终的磷酸化。在IFN-β处理的MDM中，半胱氨酸蛋白酶抑制剂B抑制了STAT-1和STAT-1 PY的核转位。这些结果表明，半胱氨酸蛋白酶抑制剂B干扰STAT-1信号传导和IFN-β-抗病毒反应，使HIV在巨噬细胞储库中永久存在。
Cystatin B is a cysteine protease inhibitor that induces HIV replication in monocyte-derived macrophages (MDM). This protein interacts with signal transducer and activator of transcription (STAT-1) factor and inhibits the interferon (IFN-β) response in Vero cells by preventing STAT-1 translocation to the nucleus. Cystatin B also decreases the levels of tyrosine-phosphorylated STAT-1 (STAT-1PY). However, the mechanisms of cystatin B regulation on STAT-1 phosphorylation in MDM are unknown. We hypothesized that cystatin B inhibits IFN-β antiviral responses and induces HIV replication in macrophage reservoirs through the inhibition of STAT-1 phosphorylation. Macrophages were transfected with cystatin B siRNA prior to interferon-β treatment or infected with HIV-ADA to determine the effect of cystatin B modulation in STAT-1 localization and activation using immunofluorescence and proximity ligation assays. Cystatin B decreased STAT-1PY and its transportation to the nucleus, while HIV infection retained unphosphorylated STAT (USTAT-1) in the nucleus avoiding its exit to the cytoplasm for eventual phosphorylation. In IFN-β-treated MDM, cystatin B inhibited the nuclear translocation of both, USTAT-1 and STAT-1PY. These results demonstrate that cystatin B interferes with the STAT-1 signaling and IFN-β-antiviral responses perpetuating HIV in macrophage reservoirs.