negative regulation of response to endoplasmic reticulum stress

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of a response to endoplasmic reticulum stress. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:11381086]

Negative regulation of response to endoplasmic reticulum (ER) stress is a crucial cellular process that ensures proper protein folding and prevents cellular dysfunction. The ER is a cellular organelle responsible for synthesizing and folding proteins. When misfolded proteins accumulate in the ER, a state known as ER stress occurs. To mitigate this stress, cells activate the unfolded protein response (UPR) pathway. However, prolonged or excessive ER stress can lead to apoptosis or cell death.

Negative regulation of response to ER stress is essential to prevent overactivation of the UPR and its potentially harmful consequences. This regulation occurs at various levels:

**1. Attenuation of UPR signaling:**
* **IRE1α (Inositol-requiring enzyme 1α)**, a key UPR sensor, initiates the XBP1 (X-box binding protein 1) splicing pathway. Once activated, IRE1α can be negatively regulated by several mechanisms. These include:
* **Ubiquitination and proteasomal degradation:** IRE1α can be targeted for degradation by ubiquitin ligases.
* **Phosphorylation:** IRE1α phosphorylation by specific kinases can inhibit its activity.
* **Feedback inhibition:** XBP1, a downstream target of IRE1α, can directly bind to the IRE1α mRNA and downregulate its translation.
* **PERK (Protein kinase R-like endoplasmic reticulum kinase)** is another UPR sensor that activates the eIF2α (eukaryotic initiation factor 2α) phosphorylation pathway.
* **Feedback inhibition:** eIF2α phosphorylation can suppress translation initiation, leading to reduced PERK activity.
* **ATF6 (Activating transcription factor 6)** is a transcription factor activated by ER stress.
* **Proteolytic processing:** ATF6 undergoes proteolytic cleavage, releasing the active form of ATF6. This process can be negatively regulated by specific proteases that cleave and inactivate ATF6.

**2. Inhibition of UPR target genes:**
* **Negative feedback loops:** The UPR targets, such as chaperones and foldases, can suppress the activation of UPR pathways.
* **MicroRNAs:** Specific microRNAs can target UPR-related transcripts, downregulating their expression.

**3. Modulation of ER homeostasis:**
* **Chaperone and foldase activity:** The UPR induces the expression of chaperones and foldases, which assist protein folding and prevent misfolding. However, excess accumulation of these proteins can be detrimental.
* **ER-associated protein degradation (ERAD):** ERAD is a quality control mechanism that targets misfolded proteins for degradation. Excess ERAD can lead to the degradation of properly folded proteins.

**4. Induction of autophagy:**
* **Autophagy:** Autophagy is a cellular process that degrades damaged or misfolded proteins. While autophagy can alleviate ER stress, excessive autophagy can be detrimental.

**5. Cellular stress response:**
* **Activation of stress-activated protein kinases (SAPKs):** SAPKs can activate pro-apoptotic pathways.
* **Activation of caspase cascades:** Caspases are proteases involved in apoptosis. Overactivation of caspases can trigger cell death.

Overall, negative regulation of response to ER stress is crucial for maintaining cellular homeostasis and preventing cell death. It involves complex regulatory mechanisms that fine-tune the UPR pathway to ensure an appropriate response to ER stress. The failure of these regulatory mechanisms can contribute to various diseases, including cancer, neurodegenerative disorders, and metabolic diseases.
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Proteins (3)

Compounds (198)