CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress.

Arindam P Ghosh,Barbara J Klocke,Mary E Ballestas,Kevin A Roth,Wael El-Rifai

doi:10.1371/journal.pone.0039586

Arindam P Ghosh, Barbara J Klocke + Show 3 more

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https://doi.org/10.1371/journal.pone.0039586

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Journal: PloS one	Publication Date: Jun 28, 2012
Citations: 237	License type: CC BY 4.0

Affiliation: University of Alabama at Birmingham

Abstract

Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in various neurodegenerative diseases including Parkinson Disease, Alzheimer Disease and Huntington Disease. PUMA (p53 upregulated modulator of apoptosis) and BIM (BCL2 interacting mediator of cell death), pro-apoptotic BH3 domain-only, BCL2 family members, have previously been shown to regulate ER stress-induced cell death, but the upstream signaling pathways that regulate this response in neuronal cells are incompletely defined. Consistent with previous studies, we show that both PUMA and BIM are induced in response to ER stress in neuronal cells and that transcriptional induction of PUMA regulates ER stress-induced cell death, independent of p53. CHOP (C/EBP homologous protein also known as GADD153; gene name Ddit3), a critical initiator of ER stress-induced apoptosis, was found to regulate both PUMA and BIM expression in response to ER stress. We further show that CHOP knockdown prevents perturbations in the AKT (protein kinase B)/FOXO3a (forkhead box, class O, 3a) pathway in response to ER stress. CHOP co-immunoprecipitated with FOXO3a in tunicamycin treated cells, suggesting that CHOP may also regulate other pro-apoptotic signaling cascades culminating in PUMA and BIM activation and cell death. In summary, CHOP regulates the expression of multiple pro-apoptotic BH3-only molecules through multiple mechanisms, making CHOP an important therapeutic target relevant to a number of neurodegenerative conditions.

Highlights

The ability to sense perturbations in the function of the Endoplasmic reticulum (ER) is critical to eukaryotic cell survival
Our current results support previous studies indicating that ER stress in neuronal cells upregulates key pro-apoptotic molecules PUMA and BIM, and that PUMA critically regulates ER stress-induced neuronal apoptosis
Our results indicate that CHOP may potentially interact with FOXO3a, a common upstream transcriptional regulator of Puma and Bim expression in neuronal cells in response to ER stress (Fig. 8), though further knockdown studies are needed in support of our preliminary data and to determine the functional significance of this interaction

Summary

Introduction

The ability to sense perturbations in the function of the ER is critical to eukaryotic cell survival. ER stress triggers an evolutionarily conserved intracellular response called the Unfolded Protein Response (UPR) in an attempt to restore cellular homeostasis [1]. The evolutionarily oldest branch of the UPR is triggered by the activation of a combined nuclease and kinase called IRE1 (inositol requiring protein-1). A second branch of the UPR is initiated by activation of the kinase PERK (protein kinase RNA (PKR)-like ER kinase), which to IRE1, responds to ER stress by autophosphorylation and homomultimerization. The UPR strives to maintain ER function during stress; if the stress is not resolved, apoptotis is activated [3,4]. Death inducing signals from the ER are integrated and amplified at the mitochondria and mouse embryonic fibroblasts from Bax 2/2Bak 2/2 mice are resistant to ER stress induced-apoptosis, indicating a critical role for BAX and BAK in ER stress-triggered death [3]. Emerging evidence has implicated ER stress-induced apoptosis in a variety of chronic diseases such as diabetes, ischemia and neurodegenerative diseases [5,6,7]

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