Recent insights into PERK-dependent signaling from the stressed endoplasmic reticulum

McQuiston, Alexander; Diehl, J. Alan

doi:10.12688/f1000research.12138.1

Cited by 82 publications

(70 citation statements)

References 97 publications

(103 reference statements)

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“…PERK is ubiquitously expressed in the body and has an ER luminal domain as well as a cytoplasmic kinase domain . BiP detachment from the ER luminal domain leads to oligomerization , trans‐autophosphorylation and activation of PERK . Active PERK phosphorylates eIF2α on serine 51 .…”

Section: Er Stress Consequencesmentioning

confidence: 99%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

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Section: Er Stress Consequencesmentioning

confidence: 99%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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“…IRE1 and PERK signaling can also trigger TXNIP signaling which activates inflammasomes. There are several review articles depicting the UPR pathways more thoroughly, both the basic pathways [1,17,26,27,31] and those related to inflammation and immunity [16,81,82]. Abbreviations: AKT, protein kinase B; AP-1, activator protein 1; ASK1, apoptosis signal-regulating kinase 1; ATF, activating transcription factor; CHOP, CCAAT-enhancer-binding protein homologous protein; eIF2α, eukaryotic initiation factor 2α; ER, endoplasmic reticulum; IκB, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; IKK, IκB kinase; IRE1, inositolrequiring protein 1; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor-κB; NOD, nucleotide-binding oligomerization domain-containing protein; PERK, protein kinase RNA-like ER kinase; TRAF2, TNF receptor-associated factor 2; TXNIP, thioredoxin-interacting protein; XBP1, X-box binding protein 1 was associated with increased ER stress and inflammation.…”

Section: Er Stress Stimulates Upr Signalingmentioning

confidence: 99%

“…The PERK transducer pathway is another signaling system which stimulates the UPR in ER stress [1,31]. The cytoplasmic protein kinase domain of PERK protein phosphorylates eukaryotic translation initiation factor-2α (eIF2α) which inhibits protein synthesis and thus alleviates the pressure of unfolded proteins in the ER (Fig.…”

Section: Er Stress Stimulates Upr Signalingmentioning

confidence: 99%

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

2020

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The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and ATF6 transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer's disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer's disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer's disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.

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“…HRI is well characterized to be activated under conditions of low heme in erythrocytes, but also can act in response to oxidative stress such as is experienced during arsenite exposure (McEwen 2005). PERK primarily signals a state of endoplasmic reticulum (ER) stress (McQuiston & Diehl 2017). PKR is activated in response to cytoplasmic double-stranded RNA during viral infection and may respond to other physiological stressors including oxidative and ER stress, and cytokine signaling (Garcia et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Chronic starvation induces non-canonical pro-death stress granules

Reineke¹,

Cheema

Dubrulle

et al. 2018

Preprint

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StatementThis work characterizes the mechanisms of formation of a novel type of stress granule that is induced in response to long-term starvation, and unlike previously described stress granules, functions in a pro-death capacity. AbstractStress granules (SGs) assemble under stress-induced conditions that inhibit protein synthesis, including eIF2α phosphorylation, inhibition of the RNA helicase eIF4a, or inactivation of mTORC1. Classically defined SGs are composed of translation initiation factors, 40S ribosomes, RNA binding proteins, and poly(A) + mRNAs, and as such represent an important compartment for storage of mRNAs and regulation of their translation. Emerging work on SGs indicates they may play important roles in cancer, neurodegenerative disease, and viral infection, often promoting survival. Yet much previous work on SGs formation and function has employed acute stress conditions, which may not accurately reflect the chronic stresses that manifest in human disease. We used prolonged nutrient starvation to investigate SG formation and function during chronic stress. Surprisingly, SGs that form under chronic nutrient starvation lack 40S ribosomes, do not actively exchange their constituent components with cytoplasmic pools, and promote cell death. These results imply that SG assembly and function in the context of prolonged nutrient starvation stress differ significantly from what has been described for acute stress conditions.

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Recent insights into PERK-dependent signaling from the stressed endoplasmic reticulum

Cited by 82 publications

References 97 publications

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

Chronic starvation induces non-canonical pro-death stress granules

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