HIV-1 Tat C-terminus is cleaved by calpain 1: implication for Tat-mediated neurotoxicity.
HIV-1 Tat C-terminus is cleaved by calpain 1: implication for Tat-mediated neurotoxicity.
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DOI：
10.1016/j.bbamcr.2008.10.010
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Peruzzi F
中科院分区：
文献类型：
--
作者：
Passiatore G;Rom S;Eletto D;Peruzzi F
HIV 脑病 (HIVE) 是一种与 HIV-1 感染和艾滋病相关的常见神经系统疾病。 HIV 反式激活蛋白 Tat 的活性被认为有助于神经元发病机制。虽然来自原代病毒分离株的 Tat 蛋白由 101 个或更多氨基酸组成，但 72 和 86 个氨基酸形式的 Tat 通常用于体外研究。尽管 Tat72 包含病毒复制所需的最小结构域，但 Tat 的其他活性似乎根据其长度、亚细胞定位、细胞类型和细胞分化阶段而变化。在本研究中，我们研究了细胞内 Tat101 在培养的神经元细胞增殖和分化过程中的稳定性。我们利用大鼠神经元祖细胞作为神经元细胞增殖和分化的模型，以及大鼠原代皮质神经元作为完全分化细胞的模型。我们的结果表明，在内化后，Tat101 在增殖细胞中比在经历神经元分化或完全分化的细胞中降解得更快。在增殖细胞和分化细胞中，钙蛋白酶 1 抑制剂 ALLN 可以阻止 Tat 的细胞内降解。钙蛋白酶抑制素肽对钙蛋白酶 1 的抑制也阻止了 Tat 裂解。体外钙蛋白酶消化和质谱分析进一步表明，对钙蛋白酶裂解敏感的 Tat 序列位于该病毒蛋白的 C 末端，氨基酸 68 和 69 之间。此外，钙蛋白酶 1 对 Tat101 的裂解增加了该病毒蛋白的神经毒性作用，钙蛋白酶抑制剂的存在可以保护神经元细胞免受 Tat 介导的毒性作用。 毒性。
HIV-Encephalopathy (HIVE) is a common neurological disorder associated with HIV-1 infection and AIDS. The activity of the HIV trans-activating protein Tat is thought to contribute to neuronal pathogenesis. While Tat proteins from primary virus isolates consist of 101 or more amino acids, 72 and 86 amino acids forms of Tat are commonly used for in vitro studies. Although Tat72 contains the minimal domain required for viral replication, other activities of Tat appear to vary according to its length, sub-cellular localization, cell type and the stage of cellular differentiation. In this study, we investigated the stability of intracellular Tat101 during proliferation and differentiation of neuronal cells in culture. We have utilized rat neuronal progenitors as a model of neuronal cell proliferation and differentiation, as well as rat primary cortical neurons as a model of fully differentiated cells. Our results indicate that, upon internalization, Tat101 was degraded more rapidly in proliferating cells than in cells which either underwent neuronal differentiation or were fully differentiated. Intracellular degradation of Tat was prevented by the calpain 1 inhibitor, ALLN, in both proliferating and differentiated cells. Inhibition of calpain 1 by calpastatin peptide also prevented Tat cleavage. In vitro calpain digestion and mass spectrometry analysis further demonstrated that the sequence of Tat sensitive to calpain cleavage was located in the C-terminus of this viral protein, between amino acids 68 and 69. Moreover, cleavage of Tat101 by calpain 1 increased neurotoxic effect of this viral protein and presence of the calpain inhibitor protected neuronal cells from Tat-mediated toxicity.
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影响因子：
5.4
作者：
Neuveut, C;Jeang, KT
通讯作者：
Jeang, KT
影响因子：
5.4
作者：
Ma, MH;Nath, A
通讯作者：
Nath, A
DOI：
10.1073/pnas.050504297
发表时间：
2000-03-14
影响因子：
11.1
作者：
Jean, F;Thomas, L;Thomas, G
通讯作者：
Thomas, G
影响因子：
11
作者：
Neuveut, C;Scoggins, RM;Jeang, KT
通讯作者：
Jeang, KT
影响因子：
4.7
作者：
Haughey, NJ;Nath, A;Geiger, JD
通讯作者：
Geiger, JD