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

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.

Impact of GADD34 on Apoptosis of Tonsillar Mononuclear Cells from IgA Nephropathy Patients by Regulating Eif2α Phosphorylation

“…Bcl-XL is an anti-apoptotic protein in Bcl-2 family proteins [47]. Research demonstrated that Bcl-XL could activate NF-κB and promote cell survival [48]. Our investigation also revealed that Bcl-XL expression was higher in IgAN group, verifying that the cell apoptosis caused by ER stress was mediated by Bcl-2 family proteins.…”

Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy

“…6,[8][9][10] Recently, in addition to the classical functions in the nucleus, the critical cytoplasmic functions of ATM have been widely reported. 22 Similarly, NF-ĸB essential modulator (NEMO), which is phosphorylated by ATM, translocates from the nucleus to the cytoplasm as the ATM-NEMO complex to activate NF-ĸB signalling. 9,12,13 In the cytoplasm, however, ATM was shown to be located in peroxisomes, mitochondria, and endosomes, [14][15][16][17][18][19] and it participates in regulating oxidative stress, cell metabolism, and autophagy.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…Surprisingly, PACS-2 has markedly different roles in its response to TRAIL compared with DNA damage; PACS2 −/− mice are impaired in TRAIL-induced apoptosis, but are sensitized to DNA-damage-induced apoptosis ; Barroso-Gonzalez et al, 2016). These opposing roles for PACS-2 are partly explained by the phosphorylation state of Ser 437 , which is reduced by TRAIL, but increased upon DNA damage (Barroso-Gonzalez et al, 2016). Whereas TRAIL uses dephosphorylated PACS-2 to induce MOMP and LMP, the DNA damage response uses phosphorylated PACS-2 to support cytostasis by coordinating NF-κB and Bcl-xL-dependent anti-apoptosis with p53-and p21 (CDKN1A)-dependent cell cycle arrest Barroso-Gonzalez et al, 2016).…”

“…Following DNA damage, cytoplasmic PACS-2 interacts with ATM, thereby sequestering the kinase in the cytoplasm where it induces TGF-β-activating kinase 1 (TAK1; also known as MAP3K7) to trigger activation of IκB kinase (IκK) (Wu et al, 2010;Barroso-Gonzalez et al, 2016) (Fig. 4D, top).…”

“…In the absence of PACS-2, ATM fails to accumulate in the cytoplasm, which reduces the induction of Bcl-xL. Consequently, induction of the apoptotic p53-Puma (Puma is also known as BBC3) pathway remains, thereby increasing MOMP and cell death (Barroso-Gonzalez et al, 2016).…”