regulation of PERK-mediated unfolded protein response

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of the PERK-mediated unfolded protein response. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:22013210]

The PERK-mediated unfolded protein response (UPR) is a critical cellular stress response triggered by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). PERK, a transmembrane protein kinase, plays a central role in this pathway. Here is a detailed breakdown of its regulation:

1. **ER Stress Recognition:** When misfolded proteins build up in the ER, they bind to the luminal domain of PERK. This binding event initiates oligomerization of PERK molecules, bringing them closer together.

2. **PERK Activation:** Oligomerization of PERK leads to its autophosphorylation, a process that activates its kinase activity.

3. **eIF2α Phosphorylation:** Activated PERK phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α). This phosphorylation event inhibits the initiation of protein translation, reducing the load of newly synthesized proteins entering the ER.

4. **ATF4 Induction:** The inhibition of translation by eIF2α phosphorylation, paradoxically, leads to an increased translation of activating transcription factor 4 (ATF4). ATF4 is a transcription factor that promotes the expression of genes involved in the UPR, including chaperones, protein folding enzymes, and genes involved in ER-associated protein degradation (ERAD).

5. **CHOP Expression:** ATF4 activates the transcription of C/EBP homologous protein (CHOP), a pro-apoptotic transcription factor. CHOP can induce apoptosis if the ER stress is severe and cannot be resolved.

6. **ERAD Activation:** The UPR also activates ERAD, a process that targets misfolded proteins for degradation by proteasomes. This helps to reduce the burden of misfolded proteins in the ER.

7. **Feedback Regulation:** The UPR is tightly regulated by a feedback mechanism. Once ER stress is resolved, PERK activity is downregulated, and eIF2α is dephosphorylated, restoring normal protein translation.

In summary, the PERK-mediated UPR is a complex and tightly regulated response to ER stress. It involves a series of events, including PERK activation, eIF2α phosphorylation, ATF4 induction, CHOP expression, and ERAD activation. This pathway aims to alleviate ER stress by reducing the load of misfolded proteins, promoting protein folding, and degrading misfolded proteins. However, if the ER stress is severe and persistent, the UPR can trigger apoptosis, contributing to cell death.'
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Proteins (1)

Compounds (10)