PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

• Published in: Cell death and differentiation 2016-09, Vol.23 (9), p.1448-1457
• Main Authors: Barroso-González, J, Auclair, S, Luan, S, Thomas, L, Atkins, K M, Aslan, J E, Thomas, L L, Zhao, J, Zhao, Y, Thomas, G
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/31; 13/95; 631/45/275; 631/80; 82/29; 82/80; Animals; Apoptosis; Apoptosis - radiation effects; Ataxia Telangiectasia Mutated Proteins - metabolism; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Caspase 3 - metabolism; Cell Biology; Cell Cycle Analysis; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage - radiation effects; HCT116 Cells; Humans; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Membranes - metabolism; NF-kappa B - metabolism; Original Paper; Radiation, Ionizing; Signal Transduction - drug effects; Stem Cells; Thymocytes - cytology; Thymocytes - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Vesicular Transport Proteins - antagonists & inhibitors; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2016.23

Nuclear factor kappa B (NF- κ B) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2 −/− thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF- κ B activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor- α -induced NF- κ B activation, suggesting a role for PACS-2 selectively in NF- κ B activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF- κ B-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.