PML is a ROS sensor activating p53 upon oxidative stress

• DOI: 10.1084/jem.20160301
• Publication Date: 2017-09-20T14:10:11Z
• Authors: Michiko Niwa-Kawa...; Omar Ferhi; Hassane Soilihi; Morgane Le Bras; Valérie Lallemand...; Hugues de Thé
• Keywords: Male; Mice, Knockout; Mice, Inbred BALB C; 0303 health sciences; Mice, 129 Strain; Microscopy, Confocal; NF-E2-Related Factor 2; Blotting, Western; Intranuclear Inclusion Bodies; [SDV.CAN]Life Sciences [q-bio]/Cancer; [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]; Promyelocytic Leukemia Protein; Embryo, Mammalian; Oxidative Stress; 03 medical and health sciences; [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]; Animals; Female; Tumor Suppressor Protein p53; Reactive Oxygen Species; Oxidation-Reduction; Research Articles; Cells, Cultured

Promyelocytic leukemia (PML) nuclear bodies (NBs) recruit partner proteins, including p53 and its regulators, thereby controlling their abundance or function. Investigating arsenic sensitivity of acute promyelocytic leukemia, we proposed that PML oxidation promotes NB biogenesis. However, physiological links between PML and oxidative stress response in vivo remain unexplored. Here, we identify PML as a reactive oxygen species (ROS) sensor. Pml−/− cells accumulate ROS, whereas PML expression decreases ROS levels. Unexpectedly, Pml−/− embryos survive acute glutathione depletion. Moreover, Pml−/− animals are resistant to acetaminophen hepatotoxicity or fasting-induced steatosis. Molecularly, Pml−/− animals fail to properly activate oxidative stress–responsive p53 targets, whereas the NRF2 response is amplified and accelerated. Finally, in an oxidative stress–prone background, Pml−/− animals display a longevity phenotype, likely reflecting decreased basal p53 activation. Thus, similar to p53, PML exerts basal antioxidant properties but also drives oxidative stress–induced changes in cell survival/proliferation or metabolism in vivo. Through NB biogenesis, PML therefore couples ROS sensing to p53 responses, shedding a new light on the role of PML in senescence or stem cell biology.