HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43.
EMBO Rep
; 25(10): 4337-4357, 2024 Oct.
Article
em En
| MEDLINE
| ID: mdl-39242776
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
HIV-1
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Proteínas de Ligação a DNA
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Caspase 3
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Proteínas do Vírus da Imunodeficiência Humana
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Proteínas Virais Reguladoras e Acessórias
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Proteólise
Limite:
Humans
Idioma:
En
Revista:
EMBO Rep
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China