2. Academic Validation
  3. HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43

HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43

  • EMBO Rep. 2024 Oct;25(10):4337-4357. doi: 10.1038/s44319-024-00238-y.
Jiaxin Yang 1,  Yan Li 1,  Huili Li 1,  Haichen Zhang 2,  Haoran Guo 1,  Xiangyu Zheng 2,  Xiao-Fang Yu 3,  Wei Wei 4 5
Affiliations

Affiliations

  • 1 Institute of Virology and AIDS Research, First Hospital, Jilin University, 130021, Changchun, Jilin, China.
  • 2 Department of Neurology and Neuroscience Center, First Hospital, Jilin University, 130021, Changchun, Jilin, China.
  • 3 Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4 Institute of Virology and AIDS Research, First Hospital, Jilin University, 130021, Changchun, Jilin, China. wwei6@jlu.edu.cn.
  • 5 Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, First Hospital, Jilin University, 130021, Changchun, Jilin, China. wwei6@jlu.edu.cn.
PMID: 39242776 DOI: 10.1038/s44319-024-00238-y
Abstract

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.

Keywords

Caspase 3; HIV-1; Neurotoxicity; TDP-43; Vpu.

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