HIV-1 subtype B Tat enhances NOTCH3 signaling in astrocytes to mediate oxidative stress, inflammatory response, and neuronal apoptosis.
Humans
Astrocytes
/ metabolism
HIV-1
/ genetics
Trans-Activators
/ metabolism
Receptor, Notch3
/ genetics
tat Gene Products, Human Immunodeficiency Virus
/ genetics
Neuroblastoma
/ metabolism
Signal Transduction
NF-kappa B
/ genetics
HIV Infections
/ genetics
Oxidative Stress
Apoptosis
Basic Helix-Loop-Helix Transcription Factors
/ metabolism
Astrocyte
HIV-associated neurocognitive disorder
Inflammatory response
NOTCH3
Oxidative stress
Tat
Journal
Journal of neurovirology
ISSN: 1538-2443
Titre abrégé: J Neurovirol
Pays: United States
ID NLM: 9508123
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
22
02
2023
accepted:
08
06
2023
revised:
02
06
2023
medline:
15
9
2023
pubmed:
26
6
2023
entrez:
26
6
2023
Statut:
ppublish
Résumé
NOTCH receptors are relevant to multiple neurodegenerative diseases. However, the roles and mechanisms of NOTCH receptors in HIV-associated neurocognitive disorder (HAND) remain largely unclear. Transactivator of transcription (Tat) induces oxidative stress and inflammatory response in astrocytes, thereby leading to neuronal apoptosis in the central nervous system. We determined that NOTCH3 expression was upregulated during subtype B or C Tat expression in HEB astroglial cells. Moreover, bioinformatics analysis of the Gene Expression Omnibus (GEO) dataset revealed that NOTCH3 mRNA expression in the frontal cortex tissues of HIV encephalitis patients was higher than that of HIV control patients. Of note, subtype B Tat, rather than subtype C Tat, interacted with the extracellular domain of the NOTCH3 receptor, thus activating NOTCH3 signaling. Downregulation of NOTCH3 attenuated subtype B Tat-induced oxidative stress and reactive oxygen species generation. In addition, we demonstrated that NOTCH3 signaling facilitated subtype B Tat-activated NF-κB signaling pathway, thereby mediating pro-inflammatory cytokines IL-6 and TNF-α production. Furthermore, downregulation of NOTCH3 in HEB astroglial cells protected SH-SY5Y neuronal cells from astrocyte-mediated subtype B Tat neurotoxicity. Taken together, our study clarifies the potential role of NOTCH3 in subtype B Tat-induced oxidative stress and inflammatory response in astrocytes, which could be a novel therapeutic target for the relief of HAND.
Identifiants
pubmed: 37358698
doi: 10.1007/s13365-023-01151-1
pii: 10.1007/s13365-023-01151-1
doi:
Substances chimiques
Trans-Activators
0
Receptor, Notch3
0
tat Gene Products, Human Immunodeficiency Virus
0
NF-kappa B
0
Basic Helix-Loop-Helix Transcription Factors
0
NOTCH3 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
479-491Informations de copyright
© 2023. The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc.
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