Endoplasmic Reticulum ER Stress Response Failure in Diseases, 2020, Bhattarai et al.

[SNT Gatchaman]

Endoplasmic Reticulum ER Stress Response Failure in Diseases
Kashi Raj Bhattarai; Manoj Chaudhary; Hyung-Ryong Kim; Han-Jung Chae

Recent work provides evidence for the new terminology, ‘endoplasmic reticulum (ER) stress response or sensing failure’, in relation to metabolic disease. We seek to identify and amass possible conditions of ER stress response failure in various metabolic and age-related pathogenesis, including obesity and diabetes.

Link | PDF (Trends in Cell Biology)

 

[SNT Gatchaman]

Selected quotes (abridged) —

• ER serves various functions, including protein synthesis, protein folding, and transporting of synthesized proteins

• physiological perturbations affect ER function, increase protein folding demand, and accumulate unfolded/misfolded proteins inside the ER lumen, which increase ER stress and trigger the unfolded protein response (UPR)

• prolonged ER stress response can activate apoptotic signals

• sensing failure also contributes to the progression of metabolic diseases where the downstream molecules involved in ER stress responses fail to be fully activated despite the activation of the upstream ER stress sensors

• chaperone HSPA5 (heat shock protein family A member 5), also called BiP/GRP78 (ER chaperone binding immunoglobulin protein/glucose-regulated protein 78 kDa), is attenuated in response to obesity and diabetes

• Similarly, the tendency of the phosphorylated PERK is high, while the downstream target phosphorylation of eIF2α and DDIT3/GADD153, or CHOP, are decreased.

• These data suggest that despite ER stress activation (as evidenced by the enhanced upstream protein), the downstream target molecules fail to be fully activated, which the authors have termed ‘ER stress response failure’

• In obese mice, a large increase in the canonical UPR sensors (IRE1α, PERK, ATF6α) was observed, suggesting the activation of chronic ER stress. Surprisingly, downstream signaling of IRE1α, sXBP1 was not activated, but rather was diminished in obese mice with strong expression of uXBP1 (unspliced).

• These data provide a presentiment that ER stress dysfunction or ER stress response failure is observed in several models of metabolic diseases

Proposed future research questions

1. Do all three branches of the UPR [IRE1α, PERK, ATF6α] need to be triggered during ER stress conditions?
2. Does the activation of upstream signaling molecules also induce ER stress despite downstream activation?
3. What could be expected for cellular fate if only upstream ER stress sensors are activated?
4. What are the possible differences in cellular conditions between the canonical ER stress and ER stress sensing failure-mediated ER stress?

 

[SNT Gatchaman]

This article referenced as #31 in WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome (2023) —

Given the importance of the interaction between the ER and mitochondria for muscle function, we reasoned that ER stress, also reported to play a role in rheumatic diseases which often feature fatigue, may regulate WASF3 in muscle cells. Indeed, the ER stress marker PERK was significantly higher while BiP was lower in the ME/CFS muscle samples. This discordance between PERK and BiP levels in ME/CFS samples suggested impairment of the canonical ER stress pathway, termed “ER Stress Response Failure,” which has been proposed to result in metabolic disorders (31).

 

[Ash]

Is there anything we can do about ER failure and get our exercise tolerance back up if that’s a factor?