title: Apoptosis Inducing Factor Binding Protein PGAM5 Triggers Mitophagic Cell Death That Is Inhibited by the Ubiquitin Ligase Activity of X-Linked Inhibitor of Apoptosis.
abstract: Apoptosis inducing factor (AIF) plays a well-defined role in controlling cell death but is also a critical factor for maintaining mitochondrial energy homeostasis; how these dueling activities are balanced has remained largely elusive. To identify new AIF binding partners that may define the continuum of AIF cellular regulation, a biochemical screen was performed that identified the mitochondrial phosphoglycerate mutase 5 (PGAM5) as an AIF associated factor. AIF binds both the short and long isoforms of PGAM5 and can reduce the ability of PGAM5 to control antioxidant responses. Transient overexpression of either PGAM5 isoform triggers caspase activation and cell death, and while AIF could reduce this caspase activation neither AIF expression nor caspase activity is required for PGAM5-mediated death. PGAM5 toxicity morphologically and biochemically resembles mitophagic cell death and is inhibited by the AIF binding protein X-linked inhibitor of apoptosis (XIAP) in a manner that depends on the ubiquitin ligase activity of XIAP. The phosphatase activity of PGAM5 was not required for cell death, and comparison of phosphatase activity between short and long PGAM5 isoforms suggested that only the long isoform is catalytically competent. This property correlated with an increased ability of PGAM5L to form dimers and/or higher order oligomers in intact cells compared to PGAM5S. Overall this study identifies an AIF/PGAM5/XIAP axis that can regulate PGAM5 activities related to the antioxidant response and mitophagy.
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157, United States.
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Lenhausen
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108, United States.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Wilkinson
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Lewis
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108, United States.
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Dailey
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Scott
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108, United States.
authors.forename: Shahzeb
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University , Fargo, North Dakota 58108, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Wilkinson
mesh_terms: D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D020033:Protein Isoforms; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D051033:Apoptosis Inducing Factor; D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D014452:Ubiquitins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases; D020169:Caspases; D008025:Ligases