endoplasmic reticulum unfolded protein response

Definition

Target type: biologicalprocess

The series of molecular signals generated as a consequence of the presence of unfolded proteins in the endoplasmic reticulum (ER) or other ER-related stress; results in changes in the regulation of transcription and translation. [GOC:mah, PMID:12042763]

The endoplasmic reticulum (ER) unfolded protein response (UPR) is a highly conserved signaling pathway that is activated in response to the accumulation of unfolded or misfolded proteins within the ER lumen. This accumulation can occur due to various stressors, including:

- **Increased protein synthesis:** When cells are actively synthesizing proteins, the ER can become overwhelmed, leading to a buildup of unfolded proteins.
- **Environmental stress:** Factors such as heat shock, oxidative stress, nutrient deprivation, and viral infection can also disrupt ER function and cause protein misfolding.
- **Mutations in proteins:** Genetic mutations that alter protein folding or stability can also contribute to the accumulation of unfolded proteins.

The UPR aims to restore ER homeostasis by:

1. **Reducing protein translation:** To decrease the influx of new proteins into the ER, the UPR activates the eIF2α kinase, which phosphorylates the translation initiation factor eIF2α. This phosphorylation reduces the translation of most mRNAs, but selectively enhances the translation of a few mRNAs, including those encoding chaperones involved in protein folding.

2. **Increasing protein folding capacity:** The UPR upregulates the expression of ER chaperones, such as BiP (GRP78), PDI, and calnexin, which assist in protein folding and prevent aggregation. These chaperones act as sensors of unfolded protein load and activate the UPR signaling cascade when their levels are overwhelmed.

3. **Degrading misfolded proteins:** The UPR activates the ER-associated protein degradation (ERAD) pathway, which removes misfolded proteins from the ER and targets them for proteasomal degradation. The ERAD pathway involves a complex machinery of proteins that recognize, extract, and retrotranslocate misfolded proteins from the ER lumen to the cytosol for ubiquitination and degradation by the proteasome.

4. **Inducing apoptosis:** If the ER stress is severe and prolonged, the UPR can trigger programmed cell death (apoptosis) to eliminate damaged cells. This apoptosis is mediated by the activation of the transcription factor CHOP, which induces the expression of pro-apoptotic genes.

The UPR is a complex and tightly regulated pathway that is essential for maintaining cellular homeostasis. While its primary function is to restore ER function, chronic or excessive activation of the UPR can lead to cellular dysfunction and disease. Dysregulation of the UPR has been implicated in a variety of diseases, including diabetes, neurodegenerative disorders, cancer, and inflammatory diseases.

The UPR is mediated by three transmembrane sensor proteins:

- **IRE1α (Inositol-requiring enzyme 1α):** IRE1α is the most conserved and abundant UPR sensor. Upon sensing misfolded proteins, IRE1α undergoes autophosphorylation and activates its endoribonuclease activity. This activity splices the mRNA encoding the transcription factor XBP1, which then translocates to the nucleus and promotes the transcription of genes involved in protein folding, ERAD, and lipid biosynthesis.

- **PERK (PKR-like endoplasmic reticulum kinase):** PERK is a serine/threonine kinase that phosphorylates the translation initiation factor eIF2α, reducing global protein synthesis. PERK activation also leads to the upregulation of the transcription factor ATF4, which promotes the expression of genes involved in amino acid metabolism, oxidative stress response, and autophagy.

- **ATF6 (Activating transcription factor 6):** ATF6 is a transcription factor that is synthesized as a transmembrane protein. In response to ER stress, ATF6 is transported to the Golgi apparatus, where it is cleaved by proteases. The cleaved ATF6 fragment translocates to the nucleus and activates the transcription of genes involved in protein folding, ERAD, and lipid biosynthesis.

The three UPR pathways are interconnected and collaborate to restore ER homeostasis. However, their specific contributions and roles vary depending on the nature and severity of the ER stress. The UPR is a dynamic and intricate process that plays a crucial role in maintaining cell survival and function.'
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Proteins (13)

Compounds (409)