negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of endoplasmic reticulum stress-induced eiF2alpha phosphorylation. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:16835242]

Negative regulation of endoplasmic reticulum (ER) stress-induced eIF2α phosphorylation is a critical cellular process that aims to restore homeostasis and prevent cell death. ER stress occurs when unfolded or misfolded proteins accumulate within the ER lumen, disrupting protein folding and causing a cascade of cellular responses. One of the key responses is the phosphorylation of eukaryotic initiation factor 2α (eIF2α), which ultimately leads to a global reduction in protein synthesis, allowing the cell to focus on protein folding and degradation. However, sustained or excessive eIF2α phosphorylation can be detrimental, leading to apoptosis.

To counter this, cells have evolved intricate mechanisms to negatively regulate eIF2α phosphorylation. These mechanisms can be broadly categorized into:

1. **Inhibition of eIF2α kinases:**
- **PERK (PKR-like ER kinase):** PERK is a transmembrane kinase that directly senses ER stress and initiates eIF2α phosphorylation. Its activity is negatively regulated by various mechanisms, including:
- **Chaperone proteins:** Binding of chaperone proteins like BiP/GRP78 to PERK prevents its activation.
- **ER stress-induced degradation:** prolonged ER stress can lead to the degradation of PERK itself.
- **Feedback inhibition:** eIF2α phosphorylation can indirectly inhibit PERK activity by affecting its localization or by promoting its degradation.
- **Other kinases:** Other kinases like GCN2 (general control nonderepressible 2) and PKR (protein kinase R) can also contribute to eIF2α phosphorylation, but their role in ER stress is generally less pronounced.
2. **Activation of eIF2α phosphatases:**
- **GADD34 (growth arrest and DNA damage-inducible 34):** GADD34 is an important regulator of eIF2α dephosphorylation. Its expression is induced by ER stress and forms a complex with the protein phosphatase PP1C, leading to the dephosphorylation of eIF2α.
- **Other phosphatases:** Other phosphatases like CReP (constitutive repressor of eIF2α phosphorylation) and PPP1R15A can also contribute to eIF2α dephosphorylation.

3. **Modulation of downstream signaling:**
- **ATF4 (activating transcription factor 4):** ATF4 is a transcription factor whose translation is enhanced by eIF2α phosphorylation. ATF4 induces the expression of genes involved in both pro-survival and pro-apoptotic pathways. Negative regulation of eIF2α phosphorylation can affect the balance between these pathways, promoting cell survival.

By fine-tuning eIF2α phosphorylation levels, cells can effectively respond to ER stress, minimizing damage and promoting cell survival. These intricate regulatory mechanisms ensure that eIF2α phosphorylation acts as a transient signal, promoting adaptation rather than sustained stress and cell death.'
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