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Apoptosis Triggered by Endoplasmic Reticulum Stress

Apoptosis, also known as programmed cell death, is a highly regulated process that plays a crucial role in maintaining tissue homeostasis and eliminating damaged or unwanted cells. It is characterized by distinct morphological and biochemical changes, including cell shrinkage, chromatin condensation, DNA fragmentation, and membrane blebbing.

Endoplasmic reticulum (ER) stress is a condition that occurs when the protein folding capacity of the ER is overwhelmed, leading to the accumulation of misfolded or unfolded proteins. This can be caused by various factors, such as nutrient deprivation, oxidative stress, calcium imbalance, viral infection, or genetic mutations.

ER Stress and the Unfolded Protein Response (UPR)

When ER stress occurs, cells activate a signaling pathway known as the unfolded protein response (UPR) to restore ER homeostasis. The UPR involves three main branches, mediated by the transmembrane proteins inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6).

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Initially, the UPR aims to alleviate ER stress by reducing protein synthesis, increasing ER chaperone production, and enhancing protein folding capacity. However, if ER stress persists or cannot be resolved, the UPR can switch from a pro-survival response to a pro-apoptotic response.

Apoptosis Signaling Pathways Activated by ER Stress

One of the key mechanisms by which ER stress triggers apoptosis is through the activation of the IRE1 branch of the UPR. Upon activation, IRE1 undergoes oligomerization and autophosphorylation, leading to the activation of its endoribonuclease activity. This results in the unconventional splicing of X-box binding protein 1 (XBP1) mRNA, generating a spliced form of XBP1 (XBP1s) that acts as a transcription factor.

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XBP1s then translocates to the nucleus and induces the expression of genes involved in ER-associated degradation (ERAD) and ER stress-induced apoptosis. These genes include CHOP (C/EBP homologous protein), which plays a crucial role in ER stress-induced apoptosis by promoting the expression of pro-apoptotic factors and inhibiting the expression of anti-apoptotic factors.

In addition to the IRE1-XBP1 pathway, ER stress can also activate the PERK branch of the UPR, leading to the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). This results in the attenuation of global protein synthesis and the selective translation of ATF4 (activating transcription factor 4). ATF4 then induces the expression of genes involved in apoptosis, such as CHOP.

Conclusion

Apoptosis triggered by endoplasmic reticulum stress is a complex process involving the activation of the unfolded protein response and the induction of pro-apoptotic signaling pathways. Understanding the molecular mechanisms underlying ER stress-induced apoptosis is important for developing therapeutic strategies to modulate cell death and promote cell survival in various diseases, including neurodegenerative disorders, cancer, and cardiovascular diseases.

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Keywords: stress, protein, apoptosis, response, unfolded, factor, apoptotic, activation, expression