Unfolded protein response in brain ischemia: A timely update

Yang, Wei; Paschen, Wulf

doi:10.1177/0271678x16674488

Cited by 58 publications

(38 citation statements)

References 80 publications

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“…The expression of ATF6 significantly increased in the mesocephalon. Activated ATF6n and XBP1s are translocated into the cell nucleus and regulated the transcription of target genes [ 32 , 42 ]. In order to verify the activation of ATF6n and XBP1s, immunohistofluorescence was used to analyze the nuclear localization of XBP1s (Fig.…”

Section: Resultsmentioning

confidence: 99%

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ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells

Tan

Zhang

Sun

et al. 2018

J Neuroinflammation

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BackgroundMany viruses depend on the extensive membranous network of the endoplasmic reticulum (ER) for their translation, replication, and packaging. Certain membrane modifications of the ER can be a trigger for ER stress, as well as the accumulation of viral protein in the ER by viral infection. Then, unfolded protein response (UPR) is activated to alleviate the stress. Zika virus (ZIKV) is a mosquito-borne flavivirus and its infection causes microcephaly in newborns and serious neurological complications in adults. Here, we investigated ER stress and the regulating model of UPR in ZIKV-infected neural cells in vitro and in vivo.MethodsMice deficient in type I and II IFN receptors were infected with ZIKV via intraperitoneal injection and the nervous tissues of the mice were assayed at 5 days post-infection. The expression of phospho-IRE1, XBP1, and ATF6 which were the key markers of ER stress were analyzed by immunohistochemistry assay in vivo. Additionally, the nuclear localization of XBP1s and ATF6n were analyzed by immunohistofluorescence. Furthermore, two representative neural cells, neuroblastoma cell line (SK-N-SH) and astrocytoma cell line (CCF-STTG1), were selected to verify the ER stress in vitro. The expression of BIP, phospho-elF2α, phospho-IRE1, and ATF6 were analyzed through western blot and the nuclear localization of XBP1s was performed by confocal immunofluorescence microscopy. RT-qPCR was also used to quantify the mRNA level of the UPR downstream genes in vitro and in vivo.ResultsZIKV infection significantly upregulated the expression of ER stress markers in vitro and in vivo. Phospho-IRE1 and XBP1 expression significantly increased in the cerebellum and mesocephalon, while ATF6 expression significantly increased in the mesocephalon. ATF6n and XBP1s were translocated into the cell nucleus. The levels of BIP, ATF6, phospho-elf2α, and spliced xbp1 also significantly increased in vitro. Furthermore, the downstream genes of UPR were detected to investigate the regulating model of the UPR during ZIKV infection in vitro and in vivo. The transcriptional levels of atf4, gadd34, chop, and edem-1 in vivo and that of gadd34 and chop in vitro significantly increased.ConclusionFindings in this study demonstrated that ZIKV infection activates ER stress in neural cells. The results offer clues to further study the mechanism of neuropathogenesis caused by ZIKV infection.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1311-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

“…Khajavi and Lupski reported that the UPR is responsible for the demyelination in peripheral neuropathy [ 31 ]. Yang and Paschen proposed that the UPR dysfunction after brain ischemia contributes to neuronal death [ 32 ]. Several studies found a clear activation of the UPR in toxicological models of Parkinson’s disease.…”

Section: Introductionmentioning

confidence: 99%

ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells

Tan

Zhang

Sun

et al. 2018

J Neuroinflammation

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“…Experimental ischemic stroke studies have shown that the capacity of cells to activate prosurvival pathways markedly declines with increasing age 8. Notably, I/R stress‐induced activation of prosurvival pathways that maintain and restore cellular protein homeostasis (proteostasis) is particularly impaired at advanced age 8, 9. On resuscitation after CA, all organs are challenged by I/R stress, and, thus, we hypothesized that aging is associated with impairment of proteostasis‐related pathways activated after CA and resuscitation.…”

Section: Introductionmentioning

confidence: 99%

“…UPR is a highly conserved pathway activated in stress conditions that impair proteostasis and result in accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) 9. The primary purpose of UPR is to restore proteostasis impaired by stress, and its activation is controlled by 3 stress sensor proteins: ATF6 (activating transcription factor 6), IRE1 (inositol‐requiring enzyme 1), and PERK (protein kinase RNA‐line ER kinase).…”

Section: Introductionmentioning

confidence: 99%

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Shen

Yan

Zhao

et al. 2018

JAHA

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BackgroundThe mechanisms underlying worse outcome at advanced age after cardiac arrest (CA) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA, we investigated the effects of age on proteostasis‐related prosurvival pathways activated after CA.Methods and ResultsYoung (2–3 months old) and aged (21–22 months old) male C57Bl/6 mice were subjected to CA and cardiopulmonary resuscitation (CPR). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level. CA/CPR‐related changes in small ubiquitin‐like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring mRNA and protein levels in the brain, kidney, and spinal cord. Thiamet‐G was used to increase O‐linked β‐N‐acetylglucosamine modification. After CA/CPR, aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin‐like modifier conjugation, ubiquitination, unfolded protein response, and O‐linked β‐N‐acetylglucosamine modification were activated after CA/CPR in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O‐linked β‐N‐acetylglucosamine modification after CA improved outcome.ConclusionsResults suggest that impaired activation of prosurvival pathways contributes to worse outcome after CA/CPR in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging‐related impairment of proteostasis‐related pathways after CA/CPR may represent a promising therapeutic strategy.

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“…To improve ischemic stroke outcome in aged brains, we tested a novel strategy for neuroprotection that boosts a pro-survival pathway in aged brains after stroke to restore neurologic function impaired by ischemic stress. We considered the unfolded protein response (UPR) as a promising target because UPR is activated to restore endoplasmic reticulum (ER) function that is impaired in a variety of stress conditions including stroke, 2–9 and because the ability to activate UPR declines with age. 10–12 …”

Section: Introductionmentioning

confidence: 99%

XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G

Jiang

Zhang

et al. 2017

Stroke

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Background and Purpose Impaired protein homeostasis induced by endoplasmic reticulum (ER) dysfunction is a key feature of a variety of age-related brain diseases including stroke. To restore ER function impaired by stress, the unfolded protein response (UPR) is activated. A key UPR pro-survival pathway is controlled by the ER stress sensor inositol-requiring enzyme-1 (IRE1), downstream X-box binding protein-1 (XBP1), and O-linked b-N-acetylglucosamine (O-GlcNAc) modification of proteins (O-GlcNAcylation). Stroke impairs ER function, which activates UPR. The rationale of this study was to explore the potentials of the IRE1/XBP1/O-GlcNAc axis as a target for neuroprotection in ischemic stroke. Methods Mice with Xbp1 loss- and gain-of-function in neurons were generated. Stroke was induced by transient or permanent occlusion of the middle cerebral artery (MCAO) in young and aged mice. Thiamet-G was used to increase O-GlcNAcylation. Results Deletion of Xbp1 worsened outcome after transient and permanent MCAO. After stroke, O-GlcNAcylation was activated in neurons of the stroke penumbra in young mice, which was largely Xbp1-dependent. This activation of O-GlcNAcylation was impaired in aged mice. Pharmacologic increase of O-GlcNAcylation before or after stroke improved outcome in both young and aged mice. Conclusions Our study indicates a critical role for the IRE1/XBP1 UPR branch in stroke outcome. O-GlcNAcylation is a pro-survival pathway that is activated in the stroke penumbra in young mice but impaired in aged mice. Boosting pro-survival pathways to counterbalance the age-related decline in the brain’s self-healing capacity could be a promising strategy to improve ischemic stroke outcome in aged brains.

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Unfolded protein response in brain ischemia: A timely update

Cited by 58 publications

References 80 publications

ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells

ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G

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