Research Article: Amyloid β‐induced elevation of O‐GlcNAcylated c‐Fos promotes neuronal cell death

Date Published: December 04, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Heesun Choi, Chaeyoung Kim, Hyundong Song, Moon‐Yong Cha, Hyun Jin Cho, Sung Min Son, Haeng Jun Kim, Inhee Mook‐Jung.

http://doi.org/10.1111/acel.12872

Abstract

Alzheimer’s disease (AD) is an age‐related neurodegenerative disease characterized by progressive memory loss resulting from cumulative neuronal cell death. O‐linked β‐N‐acetyl glucosamine (O‐GlcNAc) modification of the proteins reflecting glucose metabolism is altered in the brains of patients with AD. However, the link between altered O‐GlcNAc modification and neuronal cell death in AD is poorly understood. Here, we examined the regulation of O‐GlcNAcylation of c‐Fos and the effects of O‐GlcNAcylated c‐Fos on neuronal cell death during AD pathogenesis. We found that amyloid beta (Aβ)‐induced O‐GlcNAcylation on serine‐56 and 57 of c‐Fos was resulted from decreased interaction between c‐Fos and O‐GlcNAcase and promoted neuronal cell death. O‐GlcNAcylated c‐Fos increased its stability and potentiated the transcriptional activity through higher interaction with c‐Jun, resulting in induction of Bim expression leading to neuronal cell death. Taken together, Aβ‐induced O‐GlcNAcylation of c‐Fos plays an important role in neuronal cell death during the pathogenesis of AD.

Partial Text

Alzheimer’s disease (AD) is an age‐related neurodegenerative disease, characterized by extracellular senile plaques and intracellular neurofibrillary tangles in the brain that causes a progressive cognitive decline and neuronal cell death (Kumar, Singh, & Ekavali 2015,; Querfurth & LaFerla, 2010). Many researches showed that β‐amyloid peptides (Aβ), composing senile plaques, induce cytotoxicity such as cell death (Querfurth & LaFerla, 2010). It has been reported that c‐Fos, one of cell death regulating proteins, is increased in the brains of patients with AD (Marcus et al., 1998). c‐Fos is a transcription factor that binds to the AP‐1 site of DNA by forming a complex with members of the Jun family of proteins (Hess, Angel, & Schorpp‐Kistner, 2004). Although target genes of AP‐1 complex are involved in various processes dependent on specific stimuli (Hess et al., 2004), it is well‐known that AP‐1 complex transcribes apoptotic genes under cytotoxic conditions (Chen et al., 2015; Fernandez et al., 2005; Gillardon et al., 1996; Shaulian & Karin, 2002; Whitfield, Neame, Paquet, Bernard, & Ham, 2001; Zhang et al., 2002). However, the specific mechanism underlying the role of c‐Fos in the pathophysiology of AD is unclear.

In this study, we revealed the novel sites and functions of O‐GlcNAcylation on c‐Fos in the presence of Aβ (Figure 6h). We identified, for the first time, that S56 and S57 are the O‐GlcNAc modified sites of c‐Fos. O‐GlcNAc cycling is known to be altered in the brains of patients with AD (Forster et al., 2014; Liu et al., 2009; Wang et al., 2017; Zhu et al., 2014), and altered c‐Fos O‐GlcNAcylation caused by Aβ may be one of the consequences of disrupted O‐GlcNAc cycling. In addition, we revealed that increased c‐Fos O‐GlcNAcylation by Aβ was mediated by a reduction in the interaction between OGA and c‐Fos. Increased c‐Fos O‐GlcNAcylation plays a role in stabilizing c‐Fos itself resulting in higher transcriptional activity of c‐Fos and c‐Jun complex leading to Bim expression. Bim is an apoptotic protein that translocates to the mitochondria and forms pores to release cytochrome c triggering caspase cascade under cytotoxic conditions (Vaid, 2011). Therefore, Aβ‐induced O‐GlcNAcylation at S56 and S57 sites of c‐Fos might promote cell death through an increase in Bim expression by the binding of c‐Fos/c‐Jun complex to the AP‐1 site.

The authors declare no conflict of interest.

HC, CK, and IM‐J designed the research. HC, HS, M‐YC, and HJK performed the experiments and analyzed data. HJC and SMS served intellectual contributions about experiments and analyzing data. HC and IM‐J wrote the manuscript. IM‐J supervised the entire project.

 

Source:

http://doi.org/10.1111/acel.12872

 

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