positive regulation of PERK-mediated unfolded protein response

Definition

Target type: biologicalprocess

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

The unfolded protein response (UPR) is a cellular stress response activated by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). The PERK branch of the UPR is a key pathway involved in attenuating ER stress and restoring homeostasis. Positive regulation of PERK-mediated UPR involves a series of events that enhance PERK activation and downstream signaling.

1. **PERK dimerization and autophosphorylation:** Under normal conditions, PERK exists as an inactive monomer in the ER membrane. Accumulation of misfolded proteins in the ER lumen triggers PERK dimerization and autophosphorylation. This conformational change activates PERK's kinase activity.

2. **eIF2α phosphorylation:** Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α). Phosphorylated eIF2α inhibits the translation initiation complex, leading to a global decrease in protein synthesis. This reduction in protein translation alleviates the stress on the ER by reducing the load of newly synthesized proteins.

3. **ATF4 expression:** The eIF2α phosphorylation also leads to increased translation of ATF4, a transcription factor that plays a critical role in the UPR. ATF4 promotes the expression of genes involved in ER stress response, including chaperones, foldases, and proteins involved in ER-associated protein degradation (ERAD).

4. **CHOP expression:** ATF4 also activates the expression of C/EBP homologous protein (CHOP). CHOP is a pro-apoptotic transcription factor that promotes cell death under prolonged ER stress. However, CHOP also contributes to the adaptation response by inducing autophagy, a process that removes misfolded proteins and organelles from the cell.

5. **ER chaperone expression:** ATF4 and other transcription factors activated during the UPR induce the expression of ER chaperones, such as glucose-regulated protein 78 (GRP78) and protein disulfide isomerase (PDI). These chaperones assist in protein folding and prevent aggregation of misfolded proteins.

6. **ERAD activation:** The UPR also activates ERAD, a pathway that removes misfolded proteins from the ER and targets them for degradation by the proteasome.

7. **Feedback regulation:** The UPR is tightly regulated through feedback mechanisms. As ER stress is alleviated and protein homeostasis is restored, the UPR signaling pathway is downregulated. This ensures that the UPR is activated only when necessary and does not disrupt normal cellular function.

8. **Modulation by other signaling pathways:** The PERK-mediated UPR can be influenced by other signaling pathways, such as the mTOR pathway and the MAPK pathway. These pathways can modulate the activity of PERK and the downstream signaling events, fine-tuning the UPR response to specific cellular conditions.'
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Proteins (1)

Compounds (30)