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

J. Barroso-González, S. Auclair, S. Luan, L. Thomas, K. M. Atkins, J. E. Aslan, L. L. Thomas, J. Zhao, Y. Zhao, G. Thomas

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Nuclear factor kappa B (NF-κB) 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-κB activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-α-induced NF-κB activation, suggesting a role for PACS-2 selectively in NF-κB activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-κB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.

Original languageEnglish (US)
Pages (from-to)1448-1457
Number of pages10
JournalCell Death and Differentiation
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Barroso-González, J., Auclair, S., Luan, S., Thomas, L., Atkins, K. M., Aslan, J. E., Thomas, L. L., Zhao, J., Zhao, Y., & Thomas, G. (2016). PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage. Cell Death and Differentiation, 23(9), 1448-1457. https://doi.org/10.1038/cdd.2016.23