Tripartite containing motif 32 modulates proliferation of human neural precursor cells in HIV-1 neurodegeneration.
Tripartite containing motif 32 modulates proliferation of human neural precursor cells in HIV-1 neurodegeneration.
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DOI：
10.1038/cdd.2015.138
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发表时间：
2016-05
影响因子：
12.4
通讯作者：
Seth P
中科院分区：
文献类型：
--
作者：
Fatima M;Kumari R;Schwamborn JC;Mahadevan A;Shankar SK;Raja R;Seth P
除了神经胶质细胞外，HIV-1感染还存在于多潜能的人类神经前体细胞(HNPC)中，并诱导神经前体细胞静止。HIV-1脑感染改变了hNPC的干性，导致HIV-1脑损伤后中枢神经内源性神经修复受扰，加重了成年神经艾滋病患者痴呆的严重程度。在儿童神经艾滋病病例中，HIV-1感染神经干细胞可导致发育里程碑延迟和认知障碍。利用人胎脑hNPC的原代培养，我们对神经干细胞决定簇-包含基序32的三部分(TRIM32)在HIV-1 TAT诱导的NPC静止中的作用获得了新的见解。HNPC经HIV-1TAT急性处理后，细胞增殖受阻，但不能诱导分化。细胞定位和TRIM32水平是影响鼻咽癌细胞干性的关键因素。HIV-1Tat暴露增加了hNPC的核定位和TRIM32水平。通过研究死后收集的HIV-1血清阳性成人患者额叶皮质中TRIM32的定位和水平，以及通过HIV-1感染hNPC来验证体外研究结果。我们观察到，与年龄匹配的对照组相比，TRIM32核定位于脑室下区(SVZ)的细胞百分比增加。我们对机制的探索表明，TRIM32是miR-155的靶点，因为HIV-1 Tat下调miR-155导致TRIM32水平上调。此外，针对TRIM32的miR-155或siRNA可挽救HIV-1Tat诱导的鼻咽癌细胞的沉默。我们的发现表明，涉及miR-155和TRIM32的新的分子级联导致HIV-1Tat诱导的hNPC增殖减弱。这项研究还发现了miR-155在调节人类神经干细胞增殖方面的未知角色，有助于更好地了解hNPC和患病的大脑。
In addition to glial cells, HIV-1 infection occurs in multipotent human neural precursor cells (hNPCs) and induces quiescence in NPCs. HIV-1 infection of the brain alters hNPC stemness, leading to perturbed endogenous neurorestoration of the CNS following brain damage by HIV-1, compounding the severity of dementia in adult neuroAIDS cases. In pediatric neuroAIDS cases, HIV-1 infection of neural stem cell can lead to delayed developmental milestones and impaired cognition. Using primary cultures of human fetal brain-derived hNPCs, we gained novel insights into the role of a neural stem cell determinant, tripartite containing motif 32 (TRIM32), in HIV-1 Tat-induced quiescence of NPCs. Acute HIV-1 Tat treatment of hNPCs resulted in proliferation arrest but did not induce differentiation. Cellular localization and levels of TRIM32 are critical regulators of stemness of NPCs. HIV-1 Tat exposure increased nuclear localization and levels of TRIM32 in hNPCs. The in vitro findings were validated by studying TRIM32 localization and levels in frontal cortex of HIV-1-seropositive adult patients collected at post mortem as well as by infection of hNPCs by HIV-1. We observed increased percentage of cells with nuclear localization of TRIM32 in the subventricular zone (SVZ) as compared with age-matched controls. Our quest for probing into the mechanisms revealed that TRIM32 is targeted by miR-155 as downregulation of miR-155 by HIV-1 Tat resulted in upregulation of TRIM32 levels. Furthermore, miR-155 or siRNA against TRIM32 rescued HIV-1 Tat-induced quiescence in NPCs. Our findings suggest a novel molecular cascade involving miR-155 and TRIM32 leading to HIV-1 Tat-induced attenuated proliferation of hNPCs. The study also uncovered an unidentified role for miR-155 in modulating human neural stem cell proliferation, helping in better understanding of hNPCs and diseased brain.