The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages

Autores
Moriwaki, Kenta; Farias Luz, Nivea; Balaji, Sakthi; de Rosa, Maria Jose; O'Donnell, Carey L.; Gough, Peter J.; Bertin, John; Welsh, Raymond M.; Chan, Francis Ka Ming
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The cytokine IL-1β is intimately linked to many pathological inflammatory conditions. Mature IL-1β secretion requires cleavage by the inflammasome. Recent evidence indicates that many cell death signal adaptors have regulatory roles in inflammasome activity. These include the apoptosis inducers FADD and caspase 8, and the necroptosis kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3. PGAM5 is a mitochondrial phosphatase that has been reported to function downstream of RIPK3 to promote necroptosis and IL-1β secretion. To interrogate the biological function of PGAM5, we generated Pgam5−/− mice. We found that Pgam5−/− mice were smaller compared with wild type littermates, and male Pgam5−/− mice were born at sub-Mendelian ratio. Despite these growth and survival defects, Pgam5−/− cells responded normally to multiple inducers of apoptosis and necroptosis. Rather, we found that PGAM5 is critical for IL-1β secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus–induced IL-1β secretion was impaired in Pgam5−/− bone marrow–derived macrophages, but not in Ripk3−/− bone marrow–derived dendritic cells, indicating that PGAM5 functions independent of RIPK3 to promote inflammasome activation. Mechanistically, PGAM5 promotes ASC polymerization, maintenance of mitochondrial integrity, and optimal reactive oxygen species production in response to inflammasome signals. Hence PGAM5 is a novel regulator of inflammasome and caspase 1 activity that functions independently of RIPK3.
Fil: Moriwaki, Kenta. University of Massachussets; Estados Unidos
Fil: Farias Luz, Nivea. Universidade Federal da Bahia; Brasil. University of Massachussets; Estados Unidos
Fil: Balaji, Sakthi. University of Massachussets; Estados Unidos
Fil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: O'Donnell, Carey L.. University of Massachussets; Estados Unidos
Fil: Gough, Peter J.. Glaxo Smith Kline; Estados Unidos
Fil: Bertin, John. Glaxo Smith Kline; Estados Unidos
Fil: Welsh, Raymond M.. University of Massachussets; Estados Unidos
Fil: Chan, Francis Ka Ming. University of Massachussets; Estados Unidos
Materia
Necroptosis
Macrophages
Pgam5
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/76893
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/76893
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in MacrophagesMoriwaki, KentaFarias Luz, NiveaBalaji, Sakthide Rosa, Maria JoseO'Donnell, Carey L.Gough, Peter J.Bertin, JohnWelsh, Raymond M.Chan, Francis Ka MingNecroptosisMacrophagesPgam5https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The cytokine IL-1β is intimately linked to many pathological inflammatory conditions. Mature IL-1β secretion requires cleavage by the inflammasome. Recent evidence indicates that many cell death signal adaptors have regulatory roles in inflammasome activity. These include the apoptosis inducers FADD and caspase 8, and the necroptosis kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3. PGAM5 is a mitochondrial phosphatase that has been reported to function downstream of RIPK3 to promote necroptosis and IL-1β secretion. To interrogate the biological function of PGAM5, we generated Pgam5−/− mice. We found that Pgam5−/− mice were smaller compared with wild type littermates, and male Pgam5−/− mice were born at sub-Mendelian ratio. Despite these growth and survival defects, Pgam5−/− cells responded normally to multiple inducers of apoptosis and necroptosis. Rather, we found that PGAM5 is critical for IL-1β secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus–induced IL-1β secretion was impaired in Pgam5−/− bone marrow–derived macrophages, but not in Ripk3−/− bone marrow–derived dendritic cells, indicating that PGAM5 functions independent of RIPK3 to promote inflammasome activation. Mechanistically, PGAM5 promotes ASC polymerization, maintenance of mitochondrial integrity, and optimal reactive oxygen species production in response to inflammasome signals. Hence PGAM5 is a novel regulator of inflammasome and caspase 1 activity that functions independently of RIPK3.Fil: Moriwaki, Kenta. University of Massachussets; Estados UnidosFil: Farias Luz, Nivea. Universidade Federal da Bahia; Brasil. University of Massachussets; Estados UnidosFil: Balaji, Sakthi. University of Massachussets; Estados UnidosFil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: O'Donnell, Carey L.. University of Massachussets; Estados UnidosFil: Gough, Peter J.. Glaxo Smith Kline; Estados UnidosFil: Bertin, John. Glaxo Smith Kline; Estados UnidosFil: Welsh, Raymond M.. University of Massachussets; Estados UnidosFil: Chan, Francis Ka Ming. University of Massachussets; Estados UnidosAmerican Association of Immunologists2016-01-18info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/76893Moriwaki, Kenta; Farias Luz, Nivea; Balaji, Sakthi; de Rosa, Maria Jose; O'Donnell, Carey L.; et al.; The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages; American Association of Immunologists; Journal of Immunology; 196; 1; 18-1-2016; 407-4150022-17671550-6606CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jimmunol.org/content/196/1/407.longinfo:eu-repo/semantics/altIdentifier/doi/10.4049/jimmunol.1501662info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:02:45Zoai:ri.conicet.gov.ar:11336/76893instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:02:45.7CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
title The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
spellingShingle The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
Moriwaki, Kenta
Necroptosis
Macrophages
Pgam5
title_short The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
title_full The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
title_fullStr The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
title_full_unstemmed The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
title_sort The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
dc.creator.none.fl_str_mv Moriwaki, Kenta
Farias Luz, Nivea
Balaji, Sakthi
de Rosa, Maria Jose
O'Donnell, Carey L.
Gough, Peter J.
Bertin, John
Welsh, Raymond M.
Chan, Francis Ka Ming
author Moriwaki, Kenta
author_facet Moriwaki, Kenta
Farias Luz, Nivea
Balaji, Sakthi
de Rosa, Maria Jose
O'Donnell, Carey L.
Gough, Peter J.
Bertin, John
Welsh, Raymond M.
Chan, Francis Ka Ming
author_role author
author2 Farias Luz, Nivea
Balaji, Sakthi
de Rosa, Maria Jose
O'Donnell, Carey L.
Gough, Peter J.
Bertin, John
Welsh, Raymond M.
Chan, Francis Ka Ming
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Necroptosis
Macrophages
Pgam5
topic Necroptosis
Macrophages
Pgam5
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The cytokine IL-1β is intimately linked to many pathological inflammatory conditions. Mature IL-1β secretion requires cleavage by the inflammasome. Recent evidence indicates that many cell death signal adaptors have regulatory roles in inflammasome activity. These include the apoptosis inducers FADD and caspase 8, and the necroptosis kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3. PGAM5 is a mitochondrial phosphatase that has been reported to function downstream of RIPK3 to promote necroptosis and IL-1β secretion. To interrogate the biological function of PGAM5, we generated Pgam5−/− mice. We found that Pgam5−/− mice were smaller compared with wild type littermates, and male Pgam5−/− mice were born at sub-Mendelian ratio. Despite these growth and survival defects, Pgam5−/− cells responded normally to multiple inducers of apoptosis and necroptosis. Rather, we found that PGAM5 is critical for IL-1β secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus–induced IL-1β secretion was impaired in Pgam5−/− bone marrow–derived macrophages, but not in Ripk3−/− bone marrow–derived dendritic cells, indicating that PGAM5 functions independent of RIPK3 to promote inflammasome activation. Mechanistically, PGAM5 promotes ASC polymerization, maintenance of mitochondrial integrity, and optimal reactive oxygen species production in response to inflammasome signals. Hence PGAM5 is a novel regulator of inflammasome and caspase 1 activity that functions independently of RIPK3.
Fil: Moriwaki, Kenta. University of Massachussets; Estados Unidos
Fil: Farias Luz, Nivea. Universidade Federal da Bahia; Brasil. University of Massachussets; Estados Unidos
Fil: Balaji, Sakthi. University of Massachussets; Estados Unidos
Fil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: O'Donnell, Carey L.. University of Massachussets; Estados Unidos
Fil: Gough, Peter J.. Glaxo Smith Kline; Estados Unidos
Fil: Bertin, John. Glaxo Smith Kline; Estados Unidos
Fil: Welsh, Raymond M.. University of Massachussets; Estados Unidos
Fil: Chan, Francis Ka Ming. University of Massachussets; Estados Unidos
description The cytokine IL-1β is intimately linked to many pathological inflammatory conditions. Mature IL-1β secretion requires cleavage by the inflammasome. Recent evidence indicates that many cell death signal adaptors have regulatory roles in inflammasome activity. These include the apoptosis inducers FADD and caspase 8, and the necroptosis kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3. PGAM5 is a mitochondrial phosphatase that has been reported to function downstream of RIPK3 to promote necroptosis and IL-1β secretion. To interrogate the biological function of PGAM5, we generated Pgam5−/− mice. We found that Pgam5−/− mice were smaller compared with wild type littermates, and male Pgam5−/− mice were born at sub-Mendelian ratio. Despite these growth and survival defects, Pgam5−/− cells responded normally to multiple inducers of apoptosis and necroptosis. Rather, we found that PGAM5 is critical for IL-1β secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus–induced IL-1β secretion was impaired in Pgam5−/− bone marrow–derived macrophages, but not in Ripk3−/− bone marrow–derived dendritic cells, indicating that PGAM5 functions independent of RIPK3 to promote inflammasome activation. Mechanistically, PGAM5 promotes ASC polymerization, maintenance of mitochondrial integrity, and optimal reactive oxygen species production in response to inflammasome signals. Hence PGAM5 is a novel regulator of inflammasome and caspase 1 activity that functions independently of RIPK3.
publishDate 2016
dc.date.none.fl_str_mv 2016-01-18
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/76893
Moriwaki, Kenta; Farias Luz, Nivea; Balaji, Sakthi; de Rosa, Maria Jose; O'Donnell, Carey L.; et al.; The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages; American Association of Immunologists; Journal of Immunology; 196; 1; 18-1-2016; 407-415
0022-1767
1550-6606
CONICET Digital
CONICET
url http://hdl.handle.net/11336/76893
identifier_str_mv Moriwaki, Kenta; Farias Luz, Nivea; Balaji, Sakthi; de Rosa, Maria Jose; O'Donnell, Carey L.; et al.; The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages; American Association of Immunologists; Journal of Immunology; 196; 1; 18-1-2016; 407-415
0022-1767
1550-6606
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jimmunol.org/content/196/1/407.long
info:eu-repo/semantics/altIdentifier/doi/10.4049/jimmunol.1501662
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/vnd.openxmlformats-officedocument.wordprocessingml.document
application/pdf
dc.publisher.none.fl_str_mv American Association of Immunologists
publisher.none.fl_str_mv American Association of Immunologists
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.221938

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