Translational Repression Mediates Activation of Nuclear Factor Kappa B by Phosphorylated Translation Initiation Factor 2

New York University Medical Center, SI 3-10, 540 First Ave., New York, NY 10016, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 01/2005; 24(23):10161-8. DOI: 10.1128/MCB.24.23.10161-10168.2004
Source: PubMed


Numerous stressful conditions activate kinases that phosphorylate the alpha subunit of translation initiation factor 2 (eIF2alpha), thus attenuating mRNA translation and activating a gene expression program known as the integrated stress response. It has been noted that conditions associated with eIF2alpha phosphorylation, notably accumulation of unfolded proteins in the endoplasmic reticulum (ER), or ER stress, are also associated with activation of nuclear factor kappa B (NF-kappaB) and that eIF2alpha phosphorylation is required for NF-kappaB activation by ER stress. We have used a pharmacologically activable version of pancreatic ER kinase (PERK, an ER stress-responsive eIF2alpha kinase) to uncouple eIF2alpha phosphorylation from stress and found that phosphorylation of eIF2alpha is both necessary and sufficient to activate both NF-kappaB DNA binding and an NF-kappaB reporter gene. eIF2alpha phosphorylation-dependent NF-kappaB activation correlated with decreased levels of the inhibitor IkappaBalpha protein. Unlike canonical signaling pathways that promote IkappaBalpha phosphorylation and degradation, eIF2alpha phosphorylation did not increase phosphorylated IkappaBalpha levels or affect the stability of the protein. Pulse-chase labeling experiments indicate instead that repression of IkappaBalpha translation plays an important role in NF-kappaB activation in cells experiencing high levels of eIF2alpha phosphorylation. These studies suggest a direct role for eIF2alpha phosphorylation-dependent translational control in activating NF-kappaB during ER stress.

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    • "011 ) , the precise molecular mechanisms responsible for the cytoprotective effects of PERK signaling on oligodendrocytes in these diseases remain unknown . Several lines of evidence have suggested that PERK signaling activates the NF - κB pathway by repressing the translation of the NF - κB inhibitor IκBα during ER stress ( Jiang et al . , 2003 ; Deng et al . , 2004 ) . Activation of NF - κB , which is increasingly recognized as an anti - apoptotic transcription factor ( Karin and Lin , 2002 ; Mincheva - Tasheva and Soler , 2013 ) , has been observed in oligodendrocytes in MS and EAE lesions ( Yan and Greer , 2008 ; McGuire et al . , 2013 ) . Interestingly , recent studies have shown that PERK acti"
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    ABSTRACT: The unfolded protein response (UPR) occurs in response to endoplasmic reticulum (ER) stress caused by the accumulation of unfolded or misfolded proteins in the ER. The UPR is comprised of three signaling pathways that promote cytoprotective functions to correct ER stress; however, if ER stress cannot be resolved the UPR results in apoptosis of affected cells. The UPR is an important feature of various human diseases, including multiple sclerosis (MS). Recent studies have shown several components of the UPR are upregulated in the multiple cell types in MS lesions, including oligodendrocytes, T cells, microglia/macrophages, and astrocytes. Data from animal model studies, particularly studies of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model, imply an important role of the UPR activation in oligodendrocytes in the development of MS. In this review we will cover current literature on the UPR and the evidence for its role in the development of MS.
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    • "PERK branch of UPR can potentially induce NF-κB essentially by its eIF2α-mediated attenuation of translation; successively inhibiting the synthesis of IκBα. It was also found that half life of this inhibitor is less compared to NF-κB culminating in increased ratio of NF-κB to IκB, which facilitates NF-κB's nuclear translocation to activate its target genes in response to ER stress (Deng et al., 2004). Comparable results were also obtained by Wu et al. (2004), which demonstrated that ultraviolet light inhibits new IκBα synthesis that can be reversed by expression of an eIF2α (S51A) mutant. "
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    ABSTRACT: Execution of fundamental cellular functions demands regulated protein folding homeostasis. Endoplasmic reticulum (ER) is an active organelle existing to implement this function by folding and modifying secretory and membrane proteins. Loss of protein folding homeostasis is central to various diseases and budding evidences suggest ER stress as being a major contributor in the development or pathology of a diseased state besides other cellular stresses. The trigger for diseases may be diverse but, inflammation and/or ER stress may be basic mechanisms increasing the severity or complicating the condition of the disease. Chronic ER stress and activation of the unfolded-protein response (UPR) through endogenous or exogenous insults may result in impaired calcium and redox homeostasis, oxidative stress via protein overload thereby also influencing vital mitochondrial functions. Calcium released from the ER augments the production of mitochondrial Reactive Oxygen Species (ROS). Toxic accumulation of ROS within ER and mitochondria disturbs fundamental organelle functions. Sustained ER stress is known to potentially elicit inflammatory responses via UPR pathways. Additionally, ROS generated through inflammation or mitochondrial dysfunction could accelerate ER malfunction. Dysfunctional UPR pathways have been associated with a wide range of diseases including several neurodegenerative diseases, stroke, metabolic disorders, cancer, inflammatory disease, diabetes mellitus, cardiovascular disease, and others. In this review, we have discussed the UPR signaling pathways, and networking between ER stress-induced inflammatory pathways, oxidative stress, and mitochondrial signaling events, which further induce or exacerbate ER stress.
    Frontiers in Cellular Neuroscience 07/2014; 8:213. DOI:10.3389/fncel.2014.00213 · 4.29 Impact Factor
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    • "Following EAE induction, NOS2 and the NAD(P)H oxidase subunits Cybb/NOX2 and Ncf1 were upregulated in WT mice but not in GFAP-IκBα-dn mice, where NF-κB is selectively inactivated in astrocytes. On the other hand, activation of the NF-κB pathway in oligodendrocytes contributes to the protective effects of enhanced pancreatic endoplasmic reticulum kinase (PERK) signaling during EAE including reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration (Deng et al., 2004). PERK signaling activates NF-κB, an antiapoptotic transcription factor, by repressing the translation of IκBα, an inhibitor of NF-κB (Lin et al., 2013). "
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