Disruption of Mitochondrial-associated ER membranes by HIV-1 tat protein contributes to premature brain aging.
Disruption of Mitochondrial-associated ER membranes by HIV-1 tat protein contributes to premature brain aging.
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DOI：
10.1111/cns.14011
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发表时间：
2023-01
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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线粒体相关ER膜（MAMs）控制许多细胞功能，包括钙和脂质交换，细胞内运输和线粒体生物合成。这些功能的破坏会导致神经认知障碍，如空间记忆障碍和大脑过早老化。使用神经元细胞，我们证明了HIV-1达特蛋白对线粒体的失调。为了确定机制，我们使用神经元细胞系，并显示达特诱导MAM相关蛋白和MAM系栓蛋白的表达和相互作用的变化。添加HIV-1达特蛋白改变了MAM组分中PTPIP 51和VAPB蛋白的表达水平，但未改变整个细胞。PTPIP 51蛋白的磷酸化调节其亚细胞定位和功能。我们证明了达特蛋白促进PTPIP 51酪氨酸残基的磷酸化并阻止其与VAPB结合。用激酶抑制剂处理细胞恢复了PTPIP 51-VAPB相互作用并克服了达特的作用。这些结果表明，达特通过诱导PTPIP 51磷酸化来破坏MAM，导致活性氧积累、线粒体应激和运动改变。因此，我们得出结论，干扰MAM相关的细胞通路有助于在HIV-1感染患者中经常观察到的空间记忆障碍和过早的脑老化。 示意图说明了达特对神经元中MAMs的影响。达特影响MAM系留蛋白IP 3R和VDAC、Bap 31和Fis 1、Bap 31和Tomm 40以及PTPIP 51和VDAC之间的相互作用。受影响的MAM束缚导致ER和线粒体之间的钙转移失调和ROS增加。达特还影响PTPIP 51磷酸化，从而影响其在MAMs上的定位。激酶抑制剂吉非替尼、达沙替尼和Rp-cAMP一起可阻断PTPIP 51酪氨酸磷酸化，即使在存在达特的情况下也是如此，并可导致PTPIP 51和VAPB相互作用。
Mitochondrial‐associated ER membranes (MAMs) control many cellular functions, including calcium and lipid exchange, intracellular trafficking, and mitochondrial biogenesis. The disruption of these functions contributes to neurocognitive disorders, such as spatial memory impairment and premature brain aging. Using neuronal cells, we demonstrated that HIV‐1 Tat protein deregulates the mitochondria. To determine the mechanisms, we used a neuronal cell line and showed that Tat‐induced changes in expression and interactions of both MAM‐associated proteins and MAM tethering proteins. The addition of HIV‐1 Tat protein alters expression levels of PTPIP51 and VAPB proteins in the MAM fraction but not the whole cell. Phosphorylation of PTPIP51 protein regulates its subcellular localization and function. We demonstrated that the Tat protein promotes PTPIP51 phosphorylation on tyrosine residues and prevents its binding to VAPB. Treatment of the cells with a kinase inhibitor restores the PTPIP51‐VAPB interaction and overcomes the effect of Tat. These results suggest that Tat disrupts the MAM, through the induction of PTPIP51 phosphorylation, leading to ROS accumulation, mitochondrial stress, and altered movement. Hence, we concluded that interfering in the MAM‐associated cellular pathways contributes to spatial memory impairment and premature brain aging often observed in HIV‐1‐infected patients. Schematic illustrating the effect of Tat on MAMs in neurons. Tat affects the interaction between MAM tethering proteins IP3R and VDAC, Bap31 and Fis1, Bap31 and Tomm40, and PTPIP51 and VDAC. The affected MAM tethering leads to dysregulated calcium transfer between the ER and mitochondria and increased ROS. Tat also affects PTPIP51 phosphorylation and thus its localization to MAMs. Kinase inhibitors gefitinib, dasatinib, and Rp‐cAMPs together can block PTPIP51 tyrosine phosphorylation even in the presence of Tat and can lead to PTPIP51 and VAPB interactions.
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DOI：
10.1007/s00018-021-03785-y
发表时间：
2021-05
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Irollo E;Luchetta J;Ho C;Nash B;Meucci O
通讯作者：
Meucci O
影响因子：
7.2
作者：
Bagashev, Asen;Mukerjee, Ruma;Sawaya, Bassel E.
通讯作者：
Sawaya, Bassel E.
影响因子：
5.5
作者：
Brobeil A;Chehab R;Dietel E;Gattenlöhner S;Wimmer M
通讯作者：
Wimmer M
影响因子：
2.5
作者：
Dietel, Eric;Brobeil, Alexander;Wimmer, Monika
通讯作者：
Wimmer, Monika
影响因子：
0.8
作者：
Leah, Tom;Vazquez-Villasenor, Irina;Mortiboys, Heather
通讯作者：
Mortiboys, Heather