The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action
2016
Griveau, A | Devailly, Guillaume | Devailly, G | Eberst, L | Navaratnam, N | Le Calvé, B | Ferrand, M | Faull, P | Augert, A | Dante, R | Vanacker, J M | Vindrieux, D | Bernard, David | Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL) ; Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Centre Léon Bérard [Lyon] | Université de Lyon | Fac Med, MRC Clin Sci Ctr, Cellular Stress Grp, Hammersmith Campus ; Imperial College London | Institut de Génomique Fonctionnelle de Lyon (IGFL) ; École normale supérieure de Lyon (ENS de Lyon) ; Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Centre National de la Recherche Scientifique (CNRS) | ANR-14-CE12-0003,PROPLAGE,Rôle de la voie Progerin-PLA2R1 dans la sénescence cellulaire et le vieillissment(2014)
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.
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