negative regulation of cytoplasmic translational initiation in response to stress

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the rate of cytoplasmic translation initiation as a result of a stimulus indicating the organism is under stress. [GOC:vw, PMID:12242291]

Negative regulation of cytoplasmic translational initiation in response to stress is a cellular mechanism that downregulates protein synthesis when the cell encounters various stress conditions, such as nutrient deprivation, heat shock, oxidative stress, or viral infection. This process is crucial for cell survival as it conserves resources and prevents the production of potentially harmful proteins.

The mechanism involves a complex interplay of signaling pathways and molecular players, ultimately leading to the inhibition of translation initiation, the first step in protein synthesis. Here's a detailed description:

**1. Sensing stress:** The cell detects stress signals through various sensors, including specific kinases, transcription factors, and unfolded protein response (UPR) pathways.

**2. Signaling cascade:** Upon stress recognition, a signaling cascade is initiated, leading to the activation of key regulatory molecules, such as:

* **mTOR (mammalian target of rapamycin):** A central regulator of cell growth and metabolism. Stress signals inhibit mTOR activity, leading to the suppression of protein synthesis.
* **eIF2α (eukaryotic initiation factor 2α):** A key factor involved in translation initiation. Stress can activate kinases that phosphorylate eIF2α, rendering it inactive.
* **4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1):** A protein that binds to eIF4E, a component of the translation initiation complex. Stress signals can activate kinases that phosphorylate 4E-BP1, preventing its interaction with eIF4E and thus inhibiting translation initiation.

**3. Inhibition of translation initiation:** The activation of these regulatory molecules ultimately leads to the suppression of translation initiation.

* **eIF2α phosphorylation:** Phosphorylated eIF2α forms a complex with the guanine nucleotide exchange factor eIF2B, inhibiting its activity and reducing the availability of the active form of eIF2α, which is essential for translation initiation.
* **mTOR inhibition:** mTOR inhibition reduces the phosphorylation of 4E-BP1, allowing it to bind to eIF4E and prevent its interaction with the mRNA cap, a critical step in translation initiation.

**4. Stress response:** The downregulation of protein synthesis allows the cell to:

* **Conserve resources:** by reducing the energy expenditure required for translation.
* **Reduce the production of misfolded proteins:** which can accumulate under stress conditions and lead to cell damage.
* **Promote cellular adaptation:** by allowing the cell to focus its resources on stress-responsive pathways that help it survive and recover.

**5. Recovery:** Once the stress is alleviated, the cell can recover its translation capacity by:

* **Dephosphorylation of eIF2α:** leading to the activation of eIF2B and the release of active eIF2α.
* **Reactivation of mTOR:** leading to the phosphorylation of 4E-BP1, allowing eIF4E to bind to the mRNA cap and initiate translation.

In summary, negative regulation of cytoplasmic translational initiation in response to stress is a critical process that enables cells to survive and adapt to various stressful conditions by downregulating protein synthesis. This complex process involves a network of signaling pathways, regulatory molecules, and downstream effectors that ultimately lead to the inhibition of translation initiation, ensuring cell survival and maintaining cellular homeostasis.'
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Compounds (77)