Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death

Vosler, Peter S.; Gao, Yanqin; Brennan, Christopher S.; Yanagiya, Akiko; Gan, Yu; Cao, Guodong; Zhang, Feng; Morley, Simon; Sonenberg, Nahum; Bennett, Michael V. L.

doi:10.1073/pnas.1112635108

Cited by 27 publications

(24 citation statements)

References 27 publications

(44 reference statements)

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“…A major function of RBM3 is to stimulate GPS (Dresios et al, 2005, Liu et al, 2013) (Smart et al, 2007). Loss of GPS persists in vulnerable CA1 neurons after brain ischemia, for example, and coincides with delayed cell death (Vosler et al, 2012). Interestingly, TH has been shown to reverse aberrant GPS in injured CA1 although to the best of our knowledge the underlying mechanism(s) have not been elucidated (Yamashita et al, 1991, Widmann et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Cold stress protein RBM3 responds to temperature change in an ultra-sensitive manner in young neurons

et al. 2015

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Extremely mild hypothermia to 36.0°C is not thought to appreciably differ clinically from 37.0°C. However, it is possible that 36.0°C stimulates highly sensitive hypothermic signaling mechanism(s) and alters biochemistry. To the best of our knowledge, no such ultra-sensitive pathway/mechanisms have been described. Here we show that cold stress protein RNA Binding motif 3 (RBM3) increases in neuron and astrocyte cultures maintained at 33°C or 36°C for 24 or 48h, compared to 37°C controls. Neurons cultured at 36°C also had increased global protein synthesis (GPS). Finally, we found that melatonin or fibroblast growth factor 21 (FGF21) augmented RBM3 upregulation in young neurons cooled to 36°C. Our results show that a 1°C reduction in temperature can induce pleiotropic biochemical changes by upregulating GPS in neurons which may be mediated by RBM3 and that this process can be pharmacologically mimicked and enhanced with melatonin or FGF21.

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Section: Discussionmentioning

confidence: 99%

Cold stress protein RBM3 responds to temperature change in an ultra-sensitive manner in young neurons

et al. 2015

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“…After ischemic brain injury, protein synthesis decreases in neurons, correlated with degradation of eIF4G in vivo (Neumar et al, 1998; Vosler et al, 2011). Overexpression of eIF4G-I in cultured neurons results in increased protein synthesis, and provides protection from ischemia induced neuronal death (Vosler et al, 2011).…”

Section: Biological Effects Of Eif4g At the Level Of Tissues And Tmentioning

confidence: 99%

“…Overexpression of eIF4G-I in cultured neurons results in increased protein synthesis, and provides protection from ischemia induced neuronal death (Vosler et al, 2011). Silencing neuronal expression of eIF4G-I results in increased cell death after ischemia (Vosler et al, 2011). Ultimately, preserving eIF4G-I levels in vivo prevents tissue loss after brain injury (Neumar et al, 1998; Vosler et al, 2011).…”

Section: Biological Effects Of Eif4g At the Level Of Tissues And Tmentioning

confidence: 99%

“…Silencing neuronal expression of eIF4G-I results in increased cell death after ischemia (Vosler et al, 2011). Ultimately, preserving eIF4G-I levels in vivo prevents tissue loss after brain injury (Neumar et al, 1998; Vosler et al, 2011). Thus, effects of expression levels of eIF4G, even in a post-developmental context, are tissue- and condition-specific.…”

Section: Biological Effects Of Eif4g At the Level Of Tissues And Tmentioning

confidence: 99%

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Role of translation initiation factor 4G in lifespan regulation and age-related health

Howard

Rogers

2014

Ageing Research Reviews

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Inhibiting expression of eukaryotic translation initiation factor 4G (eIF4G) arrests normal development but extends lifespan when suppressed during adulthood. In addition to reducing overall translation, inhibition alters the stoichiometry of mRNA translation in favor of genes important for responding to stress and against those associated with growth and reproduction in C. elegans. In humans, aberrant expression of eIF4G is associated with certain forms of cancer and neurodegeneration. Here we review what is known about the roles of eIF4G in molecular, cellular, and organismal contexts. Also discussed are the gaps in understanding of this factor, particularly with regard to the roles of specific forms of expression in individual tissues and the importance of understanding eIF4G for development of potential therapeutic applications.

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“…The increased cytoplasmic degradation and nuclear accumulation of CPEB3 result in a faster decline of CPEB3 level in the cytoplasm than in the nucleus. Other translation regulators, such as dicer and eIF4G1, have also been identified as calpain substrates (38,57). This study identifies the underlying mechanism of NMDA-induced CPEB3 degradation as a prerequisite to activating CPEB3-targeted RNA translation.…”

Section: Discussionmentioning

confidence: 91%

Calpain 2 Activated through N-Methyl-d-Aspartic Acid Receptor Signaling Cleaves CPEB3 and Abrogates CPEB3-Repressed Translation in Neurons

Wang

Huang

2012

Molecular and Cellular Biology

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b Long-term memory requires the activity-dependent reorganization of the synaptic proteome to modulate synaptic efficacy and consequently consolidate memory. Activity-regulated RNA translation can change the protein composition at the stimulated synapse. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein that represses translation of its target mRNAs in neurons, while activation of N-methyl-D-aspartic acid (NMDA) receptors alleviates this repression. Although recent research has revealed the mechanism of CPEB3-inhibited translation, how NMDA receptor signaling modulates the translational activity of CPEB3 remains unclear. This study shows that the repressor CPEB3 is degraded in NMDA-stimulated neurons and that the degradation of CPEB3 is accompanied by the elevated expression of CPEB3's target, epidermal growth factor receptor (EGFR), mostly at the translational level. Using pharmacological and knockdown approaches, we have identified that calpain 2, activated by the influx of calcium through NMDA receptors, proteolyzes the N-terminal repression motif but not the C-terminal RNA-binding domain of CPEB3. As a result, the calpain 2-cleaved CPEB3 fragment binds to RNA but fails to repress translation. Therefore, the cleavage of CPEB3 by NMDA-activated calpain 2 accounts for the activityrelated translation of CPEB3-targeted RNAs. Synaptic plasticity, which is the ability of neuronal synapses to undergo morphological and functional changes in response to various stimuli, forms the underlying molecular basis of memory. Activity-induced plasticity-related protein (PRP) synthesis sustains long-lasting synapse changes that are crucial for establishing and consolidating long-term memory. Neurons employ three strategies to increase the synaptic levels of specific PRPs upon activation. PRPs are deposited at the stimulated synapses by capturing the trafficking molecules in the form of proteins or RNAs de novo synthesized from soma (20, 51). The newly delivered PRP RNAs are then translated locally at synapses (51). Alternatively, PRPs are produced through translational activation of preexisting dendritic dormant mRNAs (10,13,45). RNA-binding proteins play essential roles in the modulation of PRP production by regulating dendritic RNA transport, translation, and/or degradation (10,13,22,45). Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein in vertebrates that likely influences PRP synthesis and memory function for the following reasons. First, the Drosophila melanogaster homologue of CPEB3, Orb2, is required for the long-term conditioning of male courtship behavior (32). Clinical research has shown that a single-nucleotide polymorphism (SNP) (a T-to-C substitution) in intron 3 of CPEB3 gene affects human episodic memory. Homozygous carriers of the C allele of SNP have poorer performance in the delayed verbal memory recall tests (56). This C allele of SNP located in the CPEB3 ribozyme sequence, exhibits more than 2-fold ...

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Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death

Cited by 27 publications

References 27 publications

Cold stress protein RBM3 responds to temperature change in an ultra-sensitive manner in young neurons

Cold stress protein RBM3 responds to temperature change in an ultra-sensitive manner in young neurons

Role of translation initiation factor 4G in lifespan regulation and age-related health

Calpain 2 Activated through N-Methyl-d-Aspartic Acid Receptor Signaling Cleaves CPEB3 and Abrogates CPEB3-Repressed Translation in Neurons

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