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PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage
J Barroso-González1, S Auclair1, S Luan1
1Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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.
Insights
Phosphofurin acidic cluster sorting protein-2 (Pacs-2) is essential for DNA damage response. Pacs-2 mediates ataxia telangiectasia mutated (ATM) and nuclear factor kappa B (NF-κB) signaling to induce Bcl-xL, promoting cell survival.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Nuclear factor kappa B (NF-κB) is a key transcription factor regulating cell survival and apoptosis.
- Genotoxic stress can trigger cellular responses involving NF-κB and anti-apoptotic proteins like Bcl-xL.
- Mitochondrial outer membrane permeabilization (MOMP) is a critical event leading to apoptosis.
Purpose of the Study:
- To investigate the role of phosphofurin acidic cluster sorting protein-2 (Pacs-2) in the DNA damage response pathway.
- To elucidate the mechanism by which Pacs-2 influences NF-κB activation and Bcl-xL induction following DNA damage.
- To determine if Pacs-2's role in NF-κB activation is specific to DNA damage-induced stress.
Main Methods:
- Primary mouse thymocytes were used to study DNA damage response.
- Pacs-2 knockout (Pacs-2(-/-)) and wild-type thymocytes were compared.
- Western blotting was used to assess Bcl-xL induction.
- Flow cytometry was employed to measure MOMP and apoptosis.
- Biochemical assays investigated interactions between Pacs-2, ATM, and NF-κB.
Main Results:
- Pacs-2 deficiency resulted in blunted Bcl-xL induction following DNA damage.
- Pacs-2(-/-) thymocytes showed increased MOMP and accelerated apoptosis.
- Cytoplasmic PACS-2 interacts with ATM to promote NF-κB activation and Bcl-xL induction.
- Pacs-2 was not required for NF-κB activation induced by tumor necrosis factor-α.
Conclusions:
- Pacs-2 is essential for the induction of Bcl-xL in response to DNA damage.
- Pacs-2 acts as a mediator linking ATM and NF-κB signaling pathways.
- Pacs-2 plays a critical role in promoting cell survival by preventing apoptosis after genotoxic stress.
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