Spliced X-Box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway

Wang, Zhao V.; Deng, Yingfeng; Gao, Ningguo; Pedrozo, Zully; Li, Dan L.; Morales, Cyndi R.; Criollo, Alfredo; Luo, Xiang; Wang, Tan; Jiang, Nan; Lehrman, Mark A.; Rothermel, Beverly A.; Lee, Ann Hwee; Lavandero, Sergio; Mammen, Pradeep P.A.; Ferdous, Anwarul; Gillette, Thomas G.; Scherer, Philipp E.; Hill, Joseph A.

doi:10.1016/j.cell.2014.01.014

Cited by 331 publications

(429 citation statements)

References 52 publications

(80 reference statements)

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“…These findings suggest that aging is associated with a decline in the capacity of cells to activate these posttranslational modifications, particularly SUMOylation and O‐GlcNAcylation. Rapid activation of both modifications has been reported in various postischemic organs 6, 8, 27, 28, 29, 30. Notably, in the present study, these were the only posttranslational modifications that showed impaired activation in both brain and kidney of aged mice.…”

Section: Discussionsupporting

confidence: 66%

“…Ischemia‐induced O‐GlcNAcylation, which was evident in all post‐CA/CPR organs that we studied herein, occurs downstream of the IRE1 UPR branch 8, 29. More important, this activation was severely impaired in both brain and kidney of aged mice.…”

Section: Discussionmentioning

confidence: 72%

“…Recently, we reported that aging is associated with impaired activation of O‐GlcNAcylation in the stroke penumbra and worse outcome, and that pharmacologic activation of O‐GlcNAcylation improves stroke outcome 8. Considering that increased O‐GlcNAcylation is neuroprotective,8 cardioprotective,29 and renoprotective,30 pharmacologic boosting of O‐GlcNAcylation is expected to protect a variety of organs exposed to I/R injury, which would be particularly beneficial in CA/CPR that causes whole‐body I/R injury. Indeed, our data showed that posttreatment with thiamet‐G improved functional outcome and reduced CA1 neuronal death after CA/CPR (Figure 9).…”

Section: Discussionmentioning

confidence: 99%

“…Our observation that activation of these pathways is impaired in aged animals therefore implies that insufficient restoration of proteostasis contributes to the worse CA outcome at advanced age. Because levels of O‐GlcNAcylation affect outcomes after experimental myocardial ischemia and stroke,8, 29 and pharmacologically boosting O‐GlcNAcylation improves ischemic stroke outcome even in aged mice,8 future studies to determine whether this promising pharmacologic intervention can improve CA outcome in aged animals are warranted.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…XBP1s is a direct transcriptional activator of the hexosamine biosynthetic (HBP) pathway, via Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes [157]. This UPR-HBP axis is triggered in a variety of stress conditions, including ischemia-reperfusion (I/R) injury, where acute stimulation of Xbp1s confers robust cardio-protection in part via induction of HBP.…”

Section: Pdmentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O‐GlcNAc)

Zachara

2018

FEBS Letters

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Almost 100 years after the first descriptions of proteins conjugated to carbohydrates (mucins), several studies suggested that glycoproteins were not restricted to the serum, extracellular matrix, cell surface, or endomembrane system. In the 1980’s, key data emerged demonstrating that intracellular proteins were modified by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc). Subsequently, this modification was identified on thousands of proteins that regulate cellular processes as diverse as protein aggregation, localization, post-translational modifications, activity, and interactions. In this Review, we will highlight critical discoveries that shaped our understanding of the molecular events underpinning the impact of O-GlcNAc on protein function, the role that O-GlcNAc plays in maintaining cellular homeostasis, and our understanding of the mechanisms that regulate O-GlcNAc-cycling.

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Spliced X-Box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway

Cited by 331 publications

References 52 publications

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

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

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O‐GlcNAc)

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