scholarly journals TRAIL Receptors Serve as Stress-Associated Molecular Patterns to Promote ER-Stress-Induced Inflammation

2020 ◽  
Vol 52 (6) ◽  
pp. 714-730.e5 ◽  
Author(s):  
Graeme P. Sullivan ◽  
Hazel O’Connor ◽  
Conor M. Henry ◽  
Pavel Davidovich ◽  
Danielle M. Clancy ◽  
...  
Keyword(s):  
Er Stress ◽  
Trail Receptors ◽  
As Stress ◽  
Molecular Patterns

scholarly journals Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors

2017 ◽  
Vol 37 (10) ◽  
Author(s):  
Raffaella Iurlaro ◽  
Franziska Püschel ◽  
Clara Lucía León-Annicchiarico ◽  
Hazel O'Connor ◽  
Seamus J. Martin ◽  
...  
Keyword(s):  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Death Receptor ◽  
Metabolic Stress ◽  
Glucose Deprivation ◽  
Trail Receptor ◽  
Normal Tissues ◽  
Trail Receptors ◽  
The Unfolded Protein Response

ABSTRACT Metabolic stress occurs frequently in tumors and in normal tissues undergoing transient ischemia. Nutrient deprivation triggers, among many potential cell death-inducing pathways, an endoplasmic reticulum (ER) stress response with the induction of the integrated stress response transcription factor ATF4. However, how this results in cell death remains unknown. Here we show that glucose deprivation triggered ER stress and induced the unfolded protein response transcription factors ATF4 and CHOP. This was associated with the nontranscriptional accumulation of TRAIL receptor 1 (TRAIL-R1) (DR4) and with the ATF4-mediated, CHOP-independent induction of TRAIL-R2 (DR5), suggesting that cell death in this context may involve death receptor signaling. Consistent with this, the ablation of TRAIL-R1, TRAIL-R2, FADD, Bid, and caspase-8 attenuated cell death, although the downregulation of TRAIL did not, suggesting ligand-independent activation of TRAIL receptors. These data indicate that stress triggered by glucose deprivation promotes the ATF4-dependent upregulation of TRAIL-R2/DR5 and TRAIL receptor-mediated cell death.

scholarly journals ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras

2017 ◽  
Vol 114 (37) ◽  
pp. 9900-9905 ◽  
Author(s):  
Nicholas Blazanin ◽  
Jeongin Son ◽  
Alayna B. Craig-Lucas ◽  
Christian L. John ◽  
Kyle J. Breech ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Posttranscriptional Regulation ◽  
Tumor Development ◽  
Rnase A ◽  
Premature Senescence ◽  
Oncogenic Signaling ◽  
Oncogenic Ras ◽  
As Stress ◽  
The Unfolded Protein Response

Oncogenic Ras causes proliferation followed by premature senescence in primary cells, an initial barrier to tumor development. The role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in regulating these two cellular outcomes is poorly understood. During ER stress, the inositol requiring enzyme 1α (IRE1α) endoribonuclease (RNase), a key mediator of the UPR, cleaves Xbp1 mRNA to generate a potent transcription factor adaptive toward ER stress. However, IRE1α also promotes cleavage and degradation of ER-localized mRNAs essential for cell death. Here, we show that oncogenic HRas induces ER stress and activation of IRE1α. Reduction of ER stress or Xbp1 splicing using pharmacological, genetic, and RNAi approaches demonstrates that this adaptive response is critical for HRas-induced proliferation. Paradoxically, reduced ER stress or Xbp1 splicing promotes growth arrest and premature senescence through hyperactivation of the IRE1α RNase. Microarray analysis of IRE1α- and XBP1-depleted cells, validation using RNA cleavage assays, and 5′ RACE identified the prooncogenic basic helix–loop–helix transcription factor ID1 as an IRE1α RNase target. Further, we demonstrate that Id1 degradation by IRE1α is essential for HRas-induced premature senescence. Together, our studies point to IRE1α as an important node for posttranscriptional regulation of the early Ras phenotype that is dependent on both oncogenic signaling as well as stress signals imparted by the tumor microenvironment and could be an important mechanism driving escape from Ras-induced senescence.

scholarly journals Aggregated and hyperstable damage-associated molecular patterns are released during ER stress to modulate immune function

2019 ◽  
Author(s):  
Alexander Andersohn ◽  
M. Iveth Garcia ◽  
Ying Fan ◽  
Max C. Thompson ◽  
Askar M. Akimzhanov ◽  
...  
Keyword(s):  
Er Stress ◽  
Systemic Inflammation ◽  
Protein Misfolding ◽  
Inflammatory Responses ◽  
Traumatic Injury ◽  
Adverse Outcomes ◽  
The Unfolded Protein Response ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

AbstractChronic ER stress occurs when protein misfolding in the ER lumen remains unresolved despite activation of the unfolded protein response. We have shown that traumatic injury such as a severe burn leads to chronic ER stressin vivoleading to systemic inflammation which can last for more than a year. The mechanisms linking chronic ER stress to systemic inflammatory responses is not clear. Here we show that induction of chronic ER stress leads to the release of known and novel damage-associated molecular patterns (DAMPs). The secreted DAMPs are aggregated and markedly protease resistant. ER stress-derived DAMPs activate dendritic cells which are then capable of polarizing naïve T cells. Our findings indicate that induction of chronic ER stress may lead to the release of hyperstable DAMPs into the circulation resulting in persistent systemic inflammation and adverse outcomes.

scholarly journals Aggregated and Hyperstable Damage-Associated Molecular Patterns Are Released During ER Stress to Modulate Immune Function

2019 ◽  
Vol 7 ◽  
Author(s):  
Alexander Andersohn ◽  
M. Iveth Garcia ◽  
Ying Fan ◽  
Max C. Thompson ◽  
Askar M. Akimzhanov ◽  
...  
Keyword(s):  
Er Stress ◽  
Immune Function ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

scholarly journals Etiological Value of Sterile Inflammation in Preeclampsia: Is It a Non-Infectious Pregnancy Complication?

2021 ◽  
Vol 11 ◽  
Author(s):  
Sayani Banerjee ◽  
Zheping Huang ◽  
Zhengke Wang ◽  
Akitoshi Nakashima ◽  
Shigeru Saito ◽  
...  
Keyword(s):  
Er Stress ◽  
Pregnancy Complications ◽  
Viral Infections ◽  
High Mobility ◽  
Sterile Inflammation ◽  
Contributory Factor ◽  
Cell Free Fetal Dna ◽  
Molecular Patterns ◽  
Key Events ◽  
Damage Associated Molecular Patterns

Understanding of sterile inflammation and its associated biological triggers and diseases is still at the elementary stage. This becomes more warranted in cases where infections are not associated with the pathology. Detrimental effects of bacterial and viral infections on the immune responses at the maternal-fetal interface as well as pregnancy outcomes have been well documented. However, an infection-induced etiology is not thought to be a major contributing component to severe pregnancy complications such as preeclampsia (PE) and gestational diabetes. How is then an inflammatory signal thought to be associated with these pregnancy complications? It is not clear what type of inflammation is involved in the onset of PE-like features. We opine that sterile inflammation regulated by the inflammasome-gasdermins-caspase-1 axis is a contributory factor to the onset of PE. We hypothesize that increased production and release of damage-associated molecular patterns (DAMPs) or Alarmins such as high-mobility group box1 (HMGB1), cell-free fetal DNA, uric acid, the NOD-like receptor pyrin-containing receptor 3 (NLRP3) inflammasome, IL-1β and IL-18 occur in the PE placenta. Some of these molecules have already been observed in the placenta from women with PE. Mechanistically, emerging evidence has demonstrated that excessive placental endoplasmic reticulum (ER) stress, impaired autophagy and gasdermine D (GSDMD)-mediated intrinsic pyroptosis are key events that contribute to systemic sterile inflammation in patients with PE, especially early-onset PE (e-PE). In this review, we highlight the advances on the roles of sterile inflammation and inflammatory signaling cascades involving ER stress, autophagy deficiency and pyroptosis in PE pathophysiology. Deciphering the mechanisms underlying these inflammatory pathways may provide potential diagnostic biomarkers and facilitate the development of therapeutic strategies to treat this devastating disease.

Induction of ER stress by variants of the prohormone convertase 1 (PCSK1)-gene

2013 ◽  
Vol 8 (S 01) ◽  
Author(s):  
S Behrendt ◽  
D Löffler ◽  
R Tauscher ◽  
A Körner
Keyword(s):  
Er Stress ◽  
Prohormone Convertase ◽  
Prohormone Convertase 1 ◽  
Pcsk1 Gene

Oleate rescues INS-1E β-cells from palmitate-induced ER-stress through a reduced phosphorylation of eIF2α

2013 ◽  
Vol 8 (S 01) ◽  
Author(s):  
D Sommerweiss ◽  
T Gorski ◽  
S Laue ◽  
S Schuster ◽  
A Garten ◽  
...  
Keyword(s):  
Er Stress ◽  
Β Cells
Sign in / Sign up

Export Citation Format

Share Document