positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of an endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway. [GOC:BHF, GOC:mtg_apoptosis, GOC:rl, GOC:TermGenie, PMID:20160352]

Positive regulation of endoplasmic reticulum (ER) stress-induced intrinsic apoptotic signaling pathway is a complex process that involves a cascade of events designed to restore ER homeostasis or, if unsuccessful, to trigger programmed cell death.

1. **ER Stress Detection and Initial Signaling:** When the ER experiences stress, such as misfolded protein accumulation, calcium imbalance, or oxidative stress, it activates several key sensor proteins:
* **PERK (PKR-like ER kinase):** PERK phosphorylates eukaryotic initiation factor 2α (eIF2α), leading to a temporary halt in protein translation, reducing the ER protein load.
* **IRE1α (inositol-requiring enzyme 1α):** IRE1α splices XBP1 mRNA, generating a transcription factor that promotes expression of genes involved in ER chaperones, protein folding, and degradation.
* **ATF6 (activating transcription factor 6):** ATF6 translocates to the Golgi apparatus, where it is cleaved and activated, resulting in the transcription of genes involved in ER chaperones, protein folding, and degradation.

2. **Activation of the Intrinsic Apoptotic Pathway:** If ER stress persists and cannot be resolved, the unfolded protein response (UPR) triggers the intrinsic apoptotic pathway. This involves:
* **CHOP (C/EBP homologous protein):** CHOP is a transcription factor activated by ATF6 and IRE1α. It promotes the expression of pro-apoptotic genes and downregulates anti-apoptotic genes.
* **Caspase-12:** ER stress activates caspase-12, an initiator caspase, which triggers a cascade of caspase activation.
* **Bcl-2 family members:** ER stress can induce the expression of pro-apoptotic Bcl-2 family members (e.g., Bax, Bak) and suppress anti-apoptotic Bcl-2 family members (e.g., Bcl-2, Bcl-xL).

3. **Mitochondrial Dysfunction and Apoptosis:**
* Pro-apoptotic Bcl-2 proteins permeabilize the mitochondrial outer membrane, releasing cytochrome c and other apoptotic factors into the cytosol.
* Cytochrome c binds to Apaf-1, forming the apoptosome, which activates caspase-9.
* Caspase-9 activates effector caspases (e.g., caspase-3, caspase-7) leading to the dismantling of the cell through DNA fragmentation, nuclear breakdown, and formation of apoptotic bodies.

Overall, the positive regulation of ER stress-induced intrinsic apoptotic signaling pathway ensures a controlled and programmed cell death process when ER stress overwhelms the cell's capacity to restore homeostasis, preventing the accumulation of misfolded proteins and potential harm to the organism.'"

Proteins (4)

Compounds (96)