PACS-2 controls endoplasmic reticulum–mitochondria communication and Bid-mediated apoptosis

Simmen, Thomas; Aslan, Joseph E.; Blagoveshchenskaya, Anastassia D.; Thomas, L. Michael; Wan, Lei; Xiang, Yang; Féliciangéli, Sylvain; Hung, Chien Hui; Crump, Colin M.; Thomas, Gary

doi:10.1038/sj.emboj.7600637

Cited by 49 publications

(92 citation statements)

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“…Whereas Akt phosphorylated PACS-2 mediates homeostatic membrane traffic, death ligands trigger dephosphorylation at PACS-2 Ser 437 , which then promotes translocation of proapoptotic Bid to mitochondria and execution of apoptosis. 20,27 Thus, our finding that DNA damage stabilizes PACS-2 phosphorylation is consistent with a cytoprotective role for PACS-2 in coordinating the p53/ p21 and NF-κB/Bcl-xL pathways ( Figure 5). Future analyses of the PACS proteins are expected to provide further insight into the complex pathways that control cell-and tissue homeostasis.…”

Section: Discussionsupporting

confidence: 81%

“…PACS-2 was initially identified by its role in mediating secretory pathway traffic and formation of contacts between the ER and mitochondria to regulate interorganellar communication and autophagy. [20][21][22][23][24][25][26][27] In response to the death ligand TRAIL (TNF-related apoptosis-inducing ligand), PACS-2 becomes dephosphorylated at Ser 437 , switching PACS-2 to a proapoptotic effector that drives permeabilization of mitochondria and lysosomes, which promotes activation of executioner caspases. 20 Recent studies show that PACS-2 responds to DNA damage by promoting cell cycle arrest and cell survival.…”

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confidence: 99%

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

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 81%

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confidence: 99%

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

et al. 2016

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“…56 Full-length BID is also capable of translocation to the mitochondria in at least one case facilitated by other proteins such as PACS2. [57][58][59] At the mitochondria, full-length BID has been shown to potentiate cell death following certain apoptotic signals, suggesting that caspase cleavage is not an absolute requirement for activating BID's proapoptotic function. 58,60 Recent studies indicate that activation of BID's prodeath activity may be negatively regulated by phosphorylation.…”

Section: Proapoptotic Bidmentioning

confidence: 99%

BCL2 family in DNA damage and cell cycle control

2006

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Individual BCL2 family members couple apoptosis regulation and cell cycle control in unique ways. Antiapoptotic BCL2 and BCL-x L are antiproliferative by facilitating G0. BAX is proapoptotic and accelerates S-phase progression. The dual functions in apoptosis and cell cycle are coordinately regulated by the multi-domain BCL2 family members (MCL-1) and suggest that survival is maintained at the expense of proliferation. The role of BH3-only molecules in cell cycle is more variable. BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x L through BH3 binding. BID has biochemically separable functions in apoptosis and S-phase checkpoint, determined by posttranslational modification. p53-induced PUMA is known only to have apoptotic function. Inhibition of apoptosis is oncogenic, whereas promotion of cell cycle arrest is tumor suppressive. Paradoxically, selected BCL2 family members can be both oncogenic and tumor suppressive. Which of the dual functions predominates is lineage specific and context dependent.

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“…2 Pacs-2 is a novel gene that influences various ER functions and cell death with participation of the mitochondria. 20 The significance of these proteins in ER stress in neurological diseases are, however, so far unknown. Studies have shown that the ER harbors caspase-12 that can be specifically cleaved/activated during ER stress.…”

Section: Introductionmentioning

confidence: 99%