ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.

Interferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like modifier that binds to target proteins in a process termed ISGylation. ISG15, first described as an antiviral molecule against many viruses, participates in numerous cellular processes, from immune modulation to the regulation of genom...

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Autores: Albert, Manuel, Vazquez, Jesus, Falcón-Pérez, Juan M, Balboa, María A, Liesa, Marc, Balsinde, Jesús, Guerra, Susana
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/16471
Acceso en línea:http://hdl.handle.net/20.500.12105/16471
Access Level:acceso abierto
Palabra clave:Cytokines
Lipid Metabolism
Ubiquitins
Vaccinia
Interferons
Lipids
PPAR gamma
Vaccinia virus
Animals
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spelling ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.Albert, ManuelVazquez, JesusFalcón-Pérez, Juan MBalboa, María ALiesa, MarcBalsinde, JesúsGuerra, SusanaCytokinesLipid MetabolismUbiquitinsVacciniaInterferonsLipidsPPAR gammaVaccinia virusAnimalsInterferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like modifier that binds to target proteins in a process termed ISGylation. ISG15, first described as an antiviral molecule against many viruses, participates in numerous cellular processes, from immune modulation to the regulation of genome stability. Interestingly, the role of ISG15 as a regulator of cell metabolism has recently gained strength. We previously described ISG15 as a regulator of mitochondrial functions in bone marrow-derived macrophages (BMDMs) in the context of Vaccinia virus (VACV) infection. Here, we demonstrate that ISG15 regulates lipid metabolism in BMDMs and that ISG15 is necessary to modulate the impact of VACV infection on lipid metabolism. We show that Isg15-/- BMDMs demonstrate alterations in the levels of several key proteins of lipid metabolism that result in differences in the lipid profile compared with Isg15+/+ (wild-type [WT]) BMDMs. Specifically, Isg15-/- BMDMs present reduced levels of neutral lipids, reflected by decreased lipid droplet number. These alterations are linked to increased levels of lipases and are independent of enhanced fatty acid oxidation (FAO). Moreover, we demonstrate that VACV causes a dysregulation in the proteomes of BMDMs and alterations in the lipid content of these cells, which appear exacerbated in Isg15-/- BMDMs. Such metabolic changes are likely caused by increased expression of the metabolic regulators peroxisome proliferator-activated receptor-γ (PPARγ) and PPARγ coactivator-1α (PGC-1α). In summary, our results highlight that ISG15 controls BMDM lipid metabolism during viral infections, suggesting that ISG15 is an important host factor to restrain VACV impact on cell metabolism. IMPORTANCE The functions of ISG15 are continuously expanding, and growing evidence supports its role as a relevant modulator of cell metabolism. In this work, we highlight how the absence of ISG15 impacts macrophage lipid metabolism in the context of viral infections and how poxviruses modulate metabolism to ensure successful replication. Our results open the door to new advances in the comprehension of macrophage immunometabolism and the interaction between VACV and the host.American Society for Microbiology (ASM)Ministerio de Sanidad (España)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)20232023-09-1520222022-12-2120222022-12-21journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/16471reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/164712026-06-12T12:43:37Z
dc.title.none.fl_str_mv ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
title ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
spellingShingle ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
Albert, Manuel
Cytokines
Lipid Metabolism
Ubiquitins
Vaccinia
Interferons
Lipids
PPAR gamma
Vaccinia virus
Animals
title_short ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
title_full ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
title_fullStr ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
title_full_unstemmed ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
title_sort ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
dc.creator.none.fl_str_mv Albert, Manuel
Vazquez, Jesus
Falcón-Pérez, Juan M
Balboa, María A
Liesa, Marc
Balsinde, Jesús
Guerra, Susana
author Albert, Manuel
author_facet Albert, Manuel
Vazquez, Jesus
Falcón-Pérez, Juan M
Balboa, María A
Liesa, Marc
Balsinde, Jesús
Guerra, Susana
author_role author
author2 Vazquez, Jesus
Falcón-Pérez, Juan M
Balboa, María A
Liesa, Marc
Balsinde, Jesús
Guerra, Susana
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Sanidad (España)
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
dc.subject.none.fl_str_mv Cytokines
Lipid Metabolism
Ubiquitins
Vaccinia
Interferons
Lipids
PPAR gamma
Vaccinia virus
Animals
topic Cytokines
Lipid Metabolism
Ubiquitins
Vaccinia
Interferons
Lipids
PPAR gamma
Vaccinia virus
Animals
description Interferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like modifier that binds to target proteins in a process termed ISGylation. ISG15, first described as an antiviral molecule against many viruses, participates in numerous cellular processes, from immune modulation to the regulation of genome stability. Interestingly, the role of ISG15 as a regulator of cell metabolism has recently gained strength. We previously described ISG15 as a regulator of mitochondrial functions in bone marrow-derived macrophages (BMDMs) in the context of Vaccinia virus (VACV) infection. Here, we demonstrate that ISG15 regulates lipid metabolism in BMDMs and that ISG15 is necessary to modulate the impact of VACV infection on lipid metabolism. We show that Isg15-/- BMDMs demonstrate alterations in the levels of several key proteins of lipid metabolism that result in differences in the lipid profile compared with Isg15+/+ (wild-type [WT]) BMDMs. Specifically, Isg15-/- BMDMs present reduced levels of neutral lipids, reflected by decreased lipid droplet number. These alterations are linked to increased levels of lipases and are independent of enhanced fatty acid oxidation (FAO). Moreover, we demonstrate that VACV causes a dysregulation in the proteomes of BMDMs and alterations in the lipid content of these cells, which appear exacerbated in Isg15-/- BMDMs. Such metabolic changes are likely caused by increased expression of the metabolic regulators peroxisome proliferator-activated receptor-γ (PPARγ) and PPARγ coactivator-1α (PGC-1α). In summary, our results highlight that ISG15 controls BMDM lipid metabolism during viral infections, suggesting that ISG15 is an important host factor to restrain VACV impact on cell metabolism. IMPORTANCE The functions of ISG15 are continuously expanding, and growing evidence supports its role as a relevant modulator of cell metabolism. In this work, we highlight how the absence of ISG15 impacts macrophage lipid metabolism in the context of viral infections and how poxviruses modulate metabolism to ensure successful replication. Our results open the door to new advances in the comprehension of macrophage immunometabolism and the interaction between VACV and the host.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-12-21
2022
2022-12-21
2023
2023-09-15
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/16471
url http://hdl.handle.net/20.500.12105/16471
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology (ASM)
publisher.none.fl_str_mv American Society for Microbiology (ASM)
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.198674

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