Institute of Virology and AIDS Research, First Hospital, Jilin University, 130021, Changchun, Jilin, China.
Department of Neurology and Neuroscience Center, First Hospital, Jilin University, 130021, Changchun, Jilin, China.
EMBO Rep. 2024 Oct;25(10):4337-4357. doi: 10.1038/s44319-024-00238-y. Epub 2024 Sep 6.
Despite the efficacy of highly active antiretroviral therapy in controlling the incidence and mortality of AIDS, effective interventions for HIV-1-induced neurological damage and cognitive impairment remain elusive. In this study, we found that HIV-1 infection can induce proteolytic cleavage and aberrant aggregation of TAR DNA-binding protein 43 (TDP-43), a pathological protein associated with various severe neurological disorders. The HIV-1 accessory protein Vpu was found to be responsible for the cleavage of TDP-43, as ectopic expression of Vpu alone was sufficient to induce TDP-43 cleavage, whereas HIV-1 lacking Vpu failed to cleave TDP-43. Mechanistically, the cleavage of TDP-43 at Asp89 by HIV-1 relies on Vpu-mediated activation of Caspase 3, and pharmacological inhibition of Caspase 3 activity effectively suppressed the HIV-1-induced aggregation and neurotoxicity of TDP-43. Overall, these results suggest that TDP-43 is a conserved host target of HIV-1 Vpu and provide evidence for the involvement of TDP-43 dysregulation in the neural pathogenesis of HIV-1.
尽管高效抗逆转录病毒疗法在控制艾滋病的发病率和死亡率方面非常有效，但针对 HIV-1 引起的神经损伤和认知障碍的有效干预措施仍难以实现。在这项研究中，我们发现 HIV-1 感染可诱导 TAR DNA 结合蛋白 43（TDP-43）的蛋白水解切割和异常聚集，TDP-43 是一种与各种严重神经疾病相关的病理性蛋白。HIV-1 辅助蛋白 Vpu 被发现负责 TDP-43 的切割，因为单独异位表达 Vpu 就足以诱导 TDP-43 切割，而缺乏 Vpu 的 HIV-1 则不能切割 TDP-43。从机制上讲，HIV-1 通过 Vpu 介导的 Caspase 3 的激活来切割 TDP-43，而 Caspase 3 活性的药理学抑制可有效抑制 HIV-1 诱导的 TDP-43 聚集和神经毒性。总的来说，这些结果表明 TDP-43 是 HIV-1 Vpu 的保守宿主靶标，并为 TDP-43 失调参与 HIV-1 的神经发病机制提供了证据。
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