A lifetime of stress: ATF6 in development and homeostasis

Hillary, Robert F.; FitzGerald, Una

doi:10.1186/s12929-018-0453-1

Cited by 194 publications

(152 citation statements)

References 62 publications

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“…ATF6 is mobilized from the ER in response to ER stress, translocated to the Golgi, and processed to release its transcription factor component, which is subsequently imported into the nucleus (Ye et al, 2000;Shen et al, 2002;Nadanaka et al, 2006). ATF6 has also been shown to function in normal animal development and has been implicated in brain, muscle, cartilage, bone, uterine, and lens development as well as in adipogenesis (Hillary and FitzGerald, 2018).…”

Section: Discussionmentioning

confidence: 99%

A Functional Unfolded Protein Response Is Required for Normal Vegetative Development

2019

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The unfolded protein response (UPR) is activated in plants in response to endoplasmic reticulum stress and plays an important role in mitigating stress damage. Multiple factors act in the UPR, including the membrane-associated transcription factor, BASIC LEUCINE ZIPPER 17 (bZIP17), and the membrane-associated RNA splicing factor, INOSITOL REQUIRING ENZYME1 (IRE1). We have analyzed an Arabidopsis (Arabidopsis thaliana) ire1a ire1b bzip17 triple mutant, with defects in stress signaling, and found that the mutant is also impaired in vegetative plant growth under conditions without externally applied stress. This raised the possibility that the UPR functions in plant development in the same manner as it does in responding to stress. bZIP17 is mobilized to the nucleus in response to stress, and through the analysis of a mobilization-defective bZIP17 mutant, we found that to support normal plant development bZIP17 must be capable of mobilization. Likewise, through the analysis of ire1 mutants defective in either protein kinase or RNase activities, we found that both must be operative to promote normal development. These findings demonstrate that the UPR, which is associated with stress responses in plants, also functions under unstressed conditions to support normal development.

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Section: Discussionmentioning

confidence: 99%

A Functional Unfolded Protein Response Is Required for Normal Vegetative Development

2019

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“…ER stress triggers the translocation of ATF6 protein from the ER to the Golgi complex where its cytoplasmic domain becomes cleaved off by site 2 protease (S2P). The mature form of ATF6 is transferred into the nucleus where it acts as a transcription factor inducing not only stress-related genes, e.g., ER chaperones, ERAD components, autophagy genes, and CHOP factor but also the ER stressunrelated developmental genes [36,37]. ATF6 factor exists in two opposing isoforms, i.e., ATF6α is the transcriptional activator whereas ATF6β is the inhibitor.…”

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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“…As the name suggests, ATF6 is a transcription factor of the leucine zipper family that is localized to the ER and has a molecular weight of 50 kDa in its activated form. During ER stress, BiP dissociates from ATF6, which results in the exposure of its Golgi localization sequence [49]; ATF6 is then processed by Site-I (S1P) and Site-II (S2P) proteases followed by the release of ATF6 fragments [50]. These released ATF6 fragments enter the nucleus and induce promoters of the grp genes by activating the ER-stress-response elements [51].…”

Section: Er Transducer-activating Transcription Factor 6 (Atf6)mentioning

confidence: 99%

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

Thangameeran

Tsai

Hung

et al. 2020

Cells

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The endoplasmic reticulum (ER) is an intracellular organelle that performs multiple functions, such as lipid biosynthesis, protein folding, and maintaining intracellular calcium homeostasis. Thus, conditions wherein the ER is unable to fold proteins is defined as ER stress, and an inbuilt quality control mechanism, called the unfolded protein response (UPR), is activated during ER stress, which serves as a recovery system that inhibits protein synthesis. Further, based on the severity of ER stress, the response could involve both proapoptotic and antiapoptotic phases. Intracerebral hemorrhage (ICH) is the second most common subtype of cerebral stroke and many lines of evidence have suggested a role for the ER in major neurological disorders. The injury mechanism during ICH includes hematoma formation, which in turn leads to inflammation, elevated intracranial pressure, and edema. a proper understanding of the injury mechanism(s) is required to effectively treat ICH and closing the gap between our current understanding of ER stress mechanisms and ICH injury can lead to valuable advances in the clinical management of ICH.Cells 2020, 9, 750 2 of 20 because of cardiovascular conditions, with hypertension playing a major role. PBI is characterized by mechanical injury followed by a mass effect with the initial ictus causing physical tissue disruption that then leads to pathophysiological conditions in the brain.A sudden rise in intracranial hematoma volume causes an increase in barotrauma and reduces blood flow to the area of the ictus [4,5]. Typically, PBI is followed by SBI, which is considered as a devastating stage after ICH, and the severity of SBI depends on the rate of recovery and location of the ICH. SBI involves the neuroinflammatory response to the triggering of the coagulation cascade through activation of the immune system. The inflammation size is based on the volume and position of the hematoma [5][6][7]. The various pathological factors responsible for SBI include the host immune response, release of thrombin, release of clot components (iron and heme)

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A lifetime of stress: ATF6 in development and homeostasis

Cited by 194 publications

References 62 publications

A Functional Unfolded Protein Response Is Required for Normal Vegetative Development

A Functional Unfolded Protein Response Is Required for Normal Vegetative Development

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

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

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