The unfolded protein response (UPR) is a feedback mechanism which prevents unfolded or misfolded proteins accumulating in the lumen of the endoplasmic reticulum (ER). Some misfolding of proteins is normal and the ER can usually identify this, attempt to repair it and if this fails remove the protein through endoplasmic reticulum associated degradation (ERAD). Misfolded protein only activates UPR when it is so widespread that there is a risk of proteins aggregating (sticking together in large clumps).
The first resort of the UPR is to try and restore normal cell function. It does this by slowing protein translation to allow time to fix the damage, then it increases production of chaperone proteins which assist in protein folding. If this is unsuccessful the UPR will then activate apoptosis as a last resort causing the cell to die in a programmed way.
The UPR occurs in the lumen of the endoplasmic reticulum where proteins destined for the secretory pathway are folded and processed. It is a stress response which activates when there is a prolonged production of misfolded and unfolded proteins and the levels of these in the ER accumulate. This is usually due to either mutations in the proteins synthesised, exposure to toxins or deprivation of essential nutrients in the endoplasmic reticulum.
1. To control the production of molecular chaperones e.g. BiP. Molecular chaperones are proteins which aid the correct folding of other proteins.
2. To increase the rate of endoplasmic reticulum associated degradation (ERAD) by activating transcription of genes that encode ERAD associated proteins. As a result, more unfolded or misfolded proteins can be moved out of the ER and into the cytosol where they are degraded by proteosomes.
3. To reduce the translation of proteins via the PERK protein kinase pathway giving the ER time to remove the buildup of misfolded proteins.
The three major transducers of ER stress are IRE1, PERK and ATF6. They are controlled by a molecular chaperone BiP, discussed below.
IRE1: A transmembrane protein which is an RNase and a kinase. When ER stress occurs it phosphorylates itself which activates its RNAse activity. This processes mRNA (e.g. XBP1 in mammals to the mature form). XBP1 is a transcription factor which regulates response to ER stress at the level of gene expression.
PERK: Also an ER transmembrane protein kinase, PERK phosphorylates eIF2α. This causes less translation initiation complexes to form in the cell so less RNA is translated into protein. This reduces the "workload" for the ER.
ATF6: ATF6 is a transcription factor which in normal conditions is an ER transmembrane protein. When ER stress occurs it is translocated to the Golgi where it is cleaved to give a cytosolic fragment. Like other transcription factors, this is able to translocate to the nucleus and regulate gene transcription.
When the above mechanisms fail to decrease the levels of misfolded proteins in the ER, apoptosis is triggered as the last resort of action. Apoptosis is a type of programmed cell death. It is generally preferable for an organism for cells to die in a controlled rather than an uncontrolled way. This is because it means signalling molecules are not released into the surrounding tissues in an uncontrolled way and phagocytosis by other cells can enable the retrieval of some of the dying cells components and stored energy.
As a consequence of ER stress remaining unresolved, apoptosis is triggered and the cell dies in a controlled way before protein aggregation in the ER causes death or abnormal cell behaviour. PERK and IRE1 are both involved in this process. PERK promotes apoptosis by inducing transcription of CHOP (a pro-apoptotic transcription factor) and arrests the cell cycle by repressing translation of cyclins. IRE1 initiates a series signals which lead to activation of the caspase cascade, leading to apoptosis.
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