title: The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages.
abstract: 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.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Kenta
authors.initials: K
authors.lastname: Moriwaki
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Universidade Federal da Bahia, Salvador-State of Bahia 40110-060, Brazil; and.
authors.forename: Nivea
authors.initials: N
authors.lastname: Farias Luz
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Sakthi
authors.initials: S
authors.lastname: Balaji
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Maria Jose
authors.identifier: http://orcid.org/0000-0002-2149-6127
authors.initials: MJ
authors.lastname: De Rosa
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Carey L
authors.initials: CL
authors.lastname: O'Donnell
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19422.
authors.forename: Peter J
authors.identifier: http://orcid.org/0000-0002-5110-9300
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19422.
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; francis.chan@umassmed.edu.
authors.forename: Francis Ka-Ming
authors.identifier: http://orcid.org/0000-0002-4803-8353
authors.initials: FK
authors.lastname: Chan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology; D053181:Caspase 8 / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D053200:Fas-Associated Death Domain Protein / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
chemical_list: C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; C570696:PGAM5 protein, mouse; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D053181:Caspase 8; D020170:Caspase 1