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首页> 外文期刊>AIDS >HIV-1 trans-activator protein dysregulates IFN-gamma signaling and contributes to the suppression of autophagy induction.
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HIV-1 trans-activator protein dysregulates IFN-gamma signaling and contributes to the suppression of autophagy induction.

机译：HIV-1反式激活蛋白异常调节IFN-γ信号传导，并有助于抑制自噬诱导。

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OBJECTIVE AND DESIGN: HIV-1 transactivator protein, Tat, has been identified as an activator of HIV-1 replication. It also dysregulates cytokine production and apoptosis in T-cells. Of the various cell death processes, autophagy is a self-digestion and degradation mechanism that recycles the contents of the cytosol, including macromolecules and cellular organelles, resulting in self-repair and conservation for survival. Recent reports demonstrated that autophagosomes can be activated by interferon-gamma (IFN-gamma) to participate in immune defence by processing foreign antigens for the recognition and killing of intracellular pathogens. As we previously showed that HIV-1 Tat perturbs IFN-gamma signaling through the suppression of STAT1 phosphorylation and consequently inhibits major histocompatibility complex class-II antigen expression, we postulate that Tat plays a role in regulating autophagy. METHODS: The role of STAT1 in IFN-gamma-induced autophagy in primary human blood macrophages was examined using a small molecule inhibitor or siRNA specific for STAT1. The effect of HIV-1 Tat on autophagy was investigated by pretreating the macrophages with HIV-1 Tat and followed by IFN-gamma stimulation. The expressions of autophagy-associated genes and their effects on engulfing mycobacteria were examined. RESULTS: The activation of STAT1 resulted in IFN-gamma-induced LC3B protein expression and autophagosome formation. As postulated, HIV-1 Tat protein suppressed IFN-gamma-induced autophagy processes, including LC3B expression. Additionally, HIV-1 Tat restricted the capturing of mycobacteria by autophagosomes. CONCLUSION: HIV-1 Tat suppressed the induction of autophagy-associated genes and inhibited the formation of autophagosomes. Perturbation of such cellular processes by HIV-1 would impair the effective containment of invading pathogens, thereby providing a favorable environment for opportunistic microbes in HIV-infected individuals.
机译：目的和设计：HIV-1反式激活蛋白Tat被鉴定为HIV-1复制的激活剂。它还会异常调节T细胞中细胞因子的产生和凋亡。在各种细胞死亡过程中，自噬是一种自我消化和降解的机制，可循环利用细胞溶质（包括大分子和细胞器）的内容物，从而实现自我修复和保存生存。最近的报道表明，干扰素-γ（IFN-γ）可以激活自噬体，通过加工外来抗原识别和杀死细胞内病原体来参与免疫防御。正如我们先前显示的，HIV-1 Tat通过抑制STAT1磷酸化来干扰IFN-γ信号传导，因此抑制了主要的组织相容性复合物II类抗原的表达，我们推测Tat在调节自噬中起作用。方法：使用小分子抑制剂或STAT1特异的siRNA检测STAT1在原代人血巨噬细胞中IFN-γ诱导的自噬中的作用。通过用HIV-1 Tat预处理巨噬细胞，然后进行IFN-γ刺激，研究了HIV-1 Tat对自噬的影响。研究了自噬相关基因的表达及其对吞噬分枝杆菌的影响。结果：STAT1的激活导致IFN-γ诱导的LC3B蛋白表达和自噬体形成。如推测的那样，HIV-1 Tat蛋白抑制了IFN-γ诱导的自噬过程，包括LC3B表达。此外，HIV-1 Tat限制了自噬体对分枝杆菌的捕获。结论：HIV-1 Tat抑制了自噬相关基因的诱导，并抑制了自噬体的形成。 HIV-1对这种细胞过程的干扰会削弱对入侵病原体的有效遏制，从而为HIV感染者中的机会性微生物提供有利的环境。

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