Caspase cleavage of gasdermin E causes neuronal pyroptosis in HIV-associated neurocognitive disorder
© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
Despite effective antiretroviral therapies, 20-30% of persons with treated HIV infection develop a neurodegenerative syndrome termed HIV-associated neurocognitive disorder (HAND). HAND is driven by HIV expression coupled with inflammation in the brain but the mechanisms underlying neuronal damage and death are uncertain. The inflammasome-pyroptosis axis coordinates an inflammatory type of regulated lytic cell death that is underpinned by the caspase-activated pore-forming gasdermin proteins. The mechanisms driving neuronal pyroptosis were investigated herein in models of HAND, using multi-platform molecular and morphological approaches that included brain tissues from persons with HAND and simian immunodeficiency virus (SIV)-infected non-human primates as well as cultured human neurons. Neurons in the frontal cortices from persons with HAND showed increased cleaved gasdermin E (GSDME), which was associated with β-III tubulin degradation and increased HIV levels. Exposure of cultured human neurons to the HIV-encoded viral protein R (Vpr) elicited time-dependent cleavage of GSDME and Ninjurin-1 (NINJ1) induction with associated cell lysis that was inhibited by siRNA suppression of both proteins. Upstream of GSDME cleavage, Vpr exposure resulted in activation of caspases-1 and 3. Pretreatment of Vpr-exposed neurons with the caspase-1 inhibitor, VX-765, reduced cleavage of both caspase-3 and GSDME, resulting in diminished cell death. To validate these findings, we examined frontal cortical tissues from SIV-infected macaques, disclosing increased expression of GSDME and NINJ1 in cortical neurons, which was co-localized with caspase-3 detection in animals with neurological disease. Thus, HIV infection of the brain triggers the convergent activation of caspases-1 and -3, which results in GSDME-mediated neuronal pyroptosis in persons with HAND. These findings demonstrate a novel mechanism by which a viral infection causes pyroptotic death in neurons while also offering new diagnostic and therapeutic strategies for HAND and other neurodegenerative disorders.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:147 |
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| Enthalten in: |
Brain : a journal of neurology - 147(2024), 2 vom: 01. Feb., Seite 717-734 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fernandes, Jason P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.02.2024 Date Revised 06.03.2024 published: Print CommentIn: Brain. 2023 Dec 22;:. - PMID 38134311 Citation Status MEDLINE |
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| doi: |
10.1093/brain/awad375 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364228709 |
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| 100 | 1 | |a Fernandes, Jason P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Caspase cleavage of gasdermin E causes neuronal pyroptosis in HIV-associated neurocognitive disorder |
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| 500 | |a CommentIn: Brain. 2023 Dec 22;:. - PMID 38134311 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a Despite effective antiretroviral therapies, 20-30% of persons with treated HIV infection develop a neurodegenerative syndrome termed HIV-associated neurocognitive disorder (HAND). HAND is driven by HIV expression coupled with inflammation in the brain but the mechanisms underlying neuronal damage and death are uncertain. The inflammasome-pyroptosis axis coordinates an inflammatory type of regulated lytic cell death that is underpinned by the caspase-activated pore-forming gasdermin proteins. The mechanisms driving neuronal pyroptosis were investigated herein in models of HAND, using multi-platform molecular and morphological approaches that included brain tissues from persons with HAND and simian immunodeficiency virus (SIV)-infected non-human primates as well as cultured human neurons. Neurons in the frontal cortices from persons with HAND showed increased cleaved gasdermin E (GSDME), which was associated with β-III tubulin degradation and increased HIV levels. Exposure of cultured human neurons to the HIV-encoded viral protein R (Vpr) elicited time-dependent cleavage of GSDME and Ninjurin-1 (NINJ1) induction with associated cell lysis that was inhibited by siRNA suppression of both proteins. Upstream of GSDME cleavage, Vpr exposure resulted in activation of caspases-1 and 3. Pretreatment of Vpr-exposed neurons with the caspase-1 inhibitor, VX-765, reduced cleavage of both caspase-3 and GSDME, resulting in diminished cell death. To validate these findings, we examined frontal cortical tissues from SIV-infected macaques, disclosing increased expression of GSDME and NINJ1 in cortical neurons, which was co-localized with caspase-3 detection in animals with neurological disease. Thus, HIV infection of the brain triggers the convergent activation of caspases-1 and -3, which results in GSDME-mediated neuronal pyroptosis in persons with HAND. These findings demonstrate a novel mechanism by which a viral infection causes pyroptotic death in neurons while also offering new diagnostic and therapeutic strategies for HAND and other neurodegenerative disorders | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a HIV | |
| 650 | 4 | |a caspase | |
| 650 | 4 | |a neurodegeneration | |
| 650 | 4 | |a neuroinflammation | |
| 650 | 4 | |a neuron | |
| 650 | 4 | |a pyroptosis | |
| 650 | 7 | |a Caspases |2 NLM | |
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| 650 | 7 | |a Caspase 3 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a Gasdermins |2 NLM | |
| 650 | 7 | |a NINJ1 protein, human |2 NLM | |
| 650 | 7 | |a Nerve Growth Factors |2 NLM | |
| 650 | 7 | |a Cell Adhesion Molecules, Neuronal |2 NLM | |
| 700 | 1 | |a Branton, William G |e verfasserin |4 aut | |
| 700 | 1 | |a Cohen, Eric A |e verfasserin |4 aut | |
| 700 | 1 | |a Koopman, Gerrit |e verfasserin |4 aut | |
| 700 | 1 | |a Kondova, Ivanela |e verfasserin |4 aut | |
| 700 | 1 | |a Gelman, Benjamin B |e verfasserin |4 aut | |
| 700 | 1 | |a Power, Christopher |e verfasserin |4 aut | |
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