PubMed ID MGI Ref. ID | Title | Curated Data | Vol(Iss)Pg | ||||
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Moriwaki K; Farias Luz N; Balaji S; De Rosa MJ; O'Donnell CL; Gough PJ; Bertin J; Welsh RM; Chan FK | The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages. | J Immunol | 2016 | 196 (1) 407-15 | 5.596607 | ||
The cytokine IL-1beta is intimately linked to many pathological inflammatory conditions. Mature IL-1beta 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-1beta 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-1beta secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus-induced IL-1beta 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. |
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 12/10/2024 MGI 6.24 |
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