15.15:
The Unfolded Protein Response
When the ER-associated degradation or ERAD pathways work inefficiently, misfolded proteins accumulate in the ER and trigger the unfolded protein response or UPR.
UPR uses three transmembrane proteins, IRE1, ATF6, and PERK, as stress sensors.
These sensors detect misfolded proteins through their luminal domains and are activated. They then accelerate the clearance of misfolded proteins by relaying distress signals to the nucleus and cytoplasm.
After activation, the dimerized IRE1 signals the nucleus to upregulate chaperone production to assist in accurate protein folding.
Additionally, piled-up misfolded proteins initiate vesicular transport of ATF6 from the ER membrane to the cisternal membrane of the Golgi complex, where its cytosolic N-terminal domain is cleaved.
The released protein domain acts as a transcription factor and binds the ER response elements responsible for activating cellular protein folding and ERAD pathways.
On the contrary, activated PERK dimers phosphorylate and inhibit the eukaryotic translation initiation factor 2 alpha or eIF2ɑ, stalling protein synthesis.
Together, the activated UPR sensors use different modes to balance the synthesis and refolding of proteins to clear misfolded proteins from the ER.
15.15:
The Unfolded Protein Response
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding pathways in the cell.
UPR detectors for misfolded proteins
Each of the three UPR receptors, IRE1, PERK, and ATF6, sense misfolded proteins and manage cell processes that allow clearance of misfolded proteins from the ER. Active IRE1 is responsible for upregulating the synthesis of ERAD machinery to accelerate the export of misfolded proteins, whereas active PERK stalls ribosomes during protein synthesis. Thus, these two signaling arms manage to balance the clearance and synthesis of proteins to alleviate ER stress. At the same time, the N-terminal region of ATF6 acts as a transcription factor to signal the upregulation of ER chaperones, such as BiP, lectins, and protein disulfide isomerase. These proteins aid in either refolding of misfolded proteins or their transport back to the cytosol for degradation.
UPR and ERAD for protein homeostasis
Under normal conditions, the ERAD is active at low levels. However, when the concentration of misfolded proteins increases in the ER, the number of chaperone molecules and components of retrotranslocation machinery is insufficient to clear this protein pile up, resulting in proteotoxic stress. UPR upscales the clearance of misfolded proteins via ERAD or lysosomal degradation. If the UPR cannot restore cellular homeostasis, the cell uses JNK protein kinase and caspases to trigger apoptotic programs.
Suggested Reading
- Hwang, Jiwon, and Ling Qi. "Quality control in the endoplasmic reticulum: crosstalk between ERAD and UPR pathways." Trends in biochemical sciences 43, no. 8 (2018): 593-605.