Abstract
Altered protein homeostasis is associated with neurodegenerative diseases and acute brain injury induced under energy depletion conditions such as ischemia. The accumulation of damaged or unfolded proteins triggers the unfolded protein response (UPR), which can act as a homeostatic response or lead to cell death. However, the factors involved in turning and adaptive response into a cell death mechanism are still not well understood. Several mechanisms leading to brain injury induced by severe hypoglycemia have been described but the contribution of the UPR has been poorly studied. Cell responses triggered during both the hypoglycemia and the glucose reinfusion periods can contribute to neuronal death. Therefore, we have investigated the activation dynamics of the PERK and the IRE1α branches of the UPR and their contribution to neuronal death in a model of glucose deprivation (GD) and glucose reintroduction (GR) in cortical neurons. Results show a rapid activation of the PERK/p-eIF2α/ATF4 pathway leading to protein synthesis inhibition during GD, which contributes to neuronal adaptation, however, sustained blockade of protein synthesis during GR promotes neuronal death. On the other hand, IRE1α activation occurs early during GD due to its interaction with BAK/BAX, while ASK1 is recruited to IRE1α activation complex during GR promoting the nuclear translocation of JNK and the upregulation of Chop. Most importantly, results show that IRE1α RNase activity towards its splicing target Xbp1 mRNA occurs late after GR, precluding a homeostatic role. Instead, IRE1α activity during GR drives neuronal death by positively regulating ASK1/JNK activity through the degradation of 14-3-3 θ mRNA, a negative regulator of ASK and an adaptor protein highly expressed in brain, implicated in neuroprotection. Collectively, results describe a novel regulatory mechanism of cell death in neurons, triggered by the downregulation of 14-3-3 θ mRNA induced by the IRE1α branch of the UPR.
Highlights
The brain is a highly energy-demanding organ that depends on glucose as the main fuel for correctOfficial journal of the Cell Death Differentiation AssociationGómora-García et al Cell Death Discovery (2021)7:131 including oxidative stress, PARP activation, and autophagy[3,4,5]
PERK activation was assessed by measuring its phosphorylation at T980 and that of its target eIF2α at S51, which results in the global block of protein synthesis and the selective translation of the transcription factor ATF412
Results demonstrate for the first time that persistent activation of IRE1α drives neuronal death through downregulation of 14-3-3 θ mRNA by IRE1α regulated IRE1-dependent decay (RIDD) activity, which positively regulates the ASK1/JNK pathway
Summary
The brain is a highly energy-demanding organ that depends on glucose as the main fuel for correctOfficial journal of the Cell Death Differentiation AssociationGómora-García et al Cell Death Discovery (2021)7:131 including oxidative stress, PARP activation, and autophagy[3,4,5]. Three ER-resident transmembrane proteins orchestrate the UPR: inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase RNA (PKR)-like ER kinase (PERK). PERK activation leads to the blockade of global protein synthesis[9] and the upregulation of genes involved in the antioxidant defense, autophagy, ER protein folding, and degradation[10] through the selective translation of the activation transcription factor 4 (ATF4). IRE1 oligomerization and trans-autophosphorylation activate its RNase domain to catalyze the cleavage of the X-binding protein 1 (Xbp1) mRNA, generating the active transcription factor XBP1s13, which promotes cell survival. The RNase domain of IRE1 mediates the cleavage of multiple RNAs in a process known as regulated IRE1-dependent decay (RIDD)[14,15], which can result in apoptosis through the downregulation of mRNAs encoding key targets for protein folding as GRP7815. The role of IRE1 in UPR-induced apoptosis is well-known, the regulation of UPR targets involved in neurodegeneration has not been completely elucidated
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