title: The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action.
abstract: Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression.
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Griveau
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: G
authors.initials: G
authors.lastname: Devailly
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: L
authors.initials: L
authors.lastname: Eberst
authors.affiliation: Cellular Stress Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Navaratnam
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: B
authors.initials: B
authors.lastname: Le Calvé
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Ferrand
authors.affiliation: Biological Mass Spectrometry and Proteomics Laboratory, MRC Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Faull
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Augert
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: R
authors.initials: R
authors.lastname: Dante
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon I, CNRS UMR5242, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Vanacker
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Vindrieux
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR 5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: D
authors.identifier: 0000-0002-1557-2074
authors.initials: D
authors.lastname: Bernard
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics; D054507:Receptors, Phospholipase A2 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D004268:DNA-Binding Proteins; D053614:Janus Kinase 2; D024101:Mitochondrial Proteins; D011960:Receptors, Estrogen; D054507:Receptors, Phospholipase A2; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C516360:PLA2R1 protein, human; C499631:TFAM protein, human; C507924:JAK2 protein, human