PERK-mediated unfolded protein response

Definition

Target type: biologicalprocess

The series of molecular signals mediated by the endoplasmic reticulum membrane stress sensor PERK (PKR-like ER kinase). Begins with activation of PERK in response to endoplasmic reticulum (ER) stress and ends with regulation of a downstream cellular process, e.g. transcription. The main substrate of PERK is the translation initiation factor eIF2alpha. Serine-phosphorylation of eIF2alpha by PERK inactivates eIF2alpha and inhibits general protein translation. In addition, eIF2alpha phosphorylation preferentially increases the translation of selective mRNAs such as ATF4 (activating transcription factor 4), which up regulates a subset of UPR genes required to restore folding capacity. [GOC:bf, GOC:PARL, PMID:22013210, PMID:27629041]

The unfolded protein response (UPR) is a cellular stress response that is activated when misfolded proteins accumulate in the endoplasmic reticulum (ER). The PERK pathway is one of three major branches of the UPR, and it plays a crucial role in alleviating ER stress by reducing protein translation and increasing the production of chaperones to help fold misfolded proteins. Here's a detailed description of the PERK-mediated UPR:

1. **ER Stress Detection:** When unfolded or misfolded proteins accumulate in the ER, they bind to the luminal domain of the PERK protein, which is a transmembrane kinase located in the ER membrane.

2. **PERK Oligomerization and Activation:** The binding of misfolded proteins triggers PERK oligomerization, leading to its autophosphorylation and activation.

3. **eIF2α Phosphorylation:** Activated PERK phosphorylates the eukaryotic initiation factor 2α (eIF2α), which is a key regulator of protein translation initiation. Phosphorylation of eIF2α inhibits the formation of the ternary complex required for translation initiation, leading to a global reduction in protein synthesis.

4. **ATF4 Induction:** eIF2α phosphorylation also triggers the translation of activating transcription factor 4 (ATF4). ATF4 is a transcription factor that upregulates the expression of genes involved in several UPR responses, including:
- **Chaperone Protein Synthesis:** ATF4 increases the expression of chaperone proteins like BiP (also known as GRP78) and GRP94, which help fold misfolded proteins in the ER.
- **ERAD Pathway Activation:** ATF4 enhances the expression of components of the ER-associated degradation (ERAD) pathway, which helps remove misfolded proteins from the ER and target them for degradation by the proteasome.
- **Amino Acid Metabolism:** ATF4 induces genes involved in amino acid biosynthesis, providing building blocks for protein synthesis.
- **Apoptosis Pathway Activation:** In prolonged or severe ER stress, ATF4 can also activate genes involved in apoptosis (programmed cell death).

5. **ATF6 Activation:** ATF6 is another transcription factor involved in the UPR, and its activation is also triggered by ER stress. However, ATF6 activation occurs through a different mechanism. Misfolded proteins in the ER cause ATF6 to be transported to the Golgi apparatus, where it is cleaved to release its active transcription factor domain. This domain then enters the nucleus and upregulates the expression of genes involved in UPR responses, including chaperone proteins and ERAD components.

6. **Feedback Regulation:** The UPR pathways are tightly regulated by feedback mechanisms to ensure appropriate responses to ER stress. Once the ER stress is resolved, the UPR is shut down to prevent excessive or prolonged activation, which can be detrimental to the cell.

In summary, the PERK-mediated UPR is a complex and essential cellular response to ER stress. It aims to alleviate stress by reducing protein translation, increasing chaperone protein synthesis, and enhancing the degradation of misfolded proteins. This complex interplay of signaling events ensures the maintenance of ER homeostasis and cell survival.'
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Proteins (2)

Compounds (28)