14.4 The Cellular Stress Response [in progress]
Key Concepts
By the end of this section, you will be able to do the following:
- Describe how the conserved cellular stress response is activated
- Explain which types of stress can activate this response
- Describe the relationship between the unfolded protein response, ER-associated protein degradation, autophagy, and apoptosis
As you have probably gathered, there are many possible recovery mechanisms that cells can use to mitigate stress-induced damage. How are these mechanisms regulated? Many eukaryotic cells exhibit a conserved cellular stress response (CSR), which coordinates multiple mechanisms to detect and respond to damage within cells. The CSR is triggered by the presence of denatured proteins (misfolded or unfolded). As discussed in Chapter 14.2, most stressors can cause damage to proteins. For example, we can see protein denaturation during to oxidative stress, osmotic stress, extreme temperature stress, and freezing. Therefore, multiple types of stress can activate the CSR. Once activated, the CSR will activate some processes and inactivate others to ensure that the appropriate mechanisms are employed to restore normal cell function. Most of these mechanisms are targeted at restoring proper protein function, which will be our focus here.
Unfolded protein response
A major portion of the CSR is the response to unfolded proteins. The endoplasmic reticulum plays an important role in detecting unfolded proteins, because a large portion of most cellular protein is translated on the rough endoplasmic reticulum (RER) membrane by ribosomes. These proteins fold inside the RER lumen. Any stress that causes protein denaturation will be detectable within the RER lumen, and proteins within the RER membrane will initiate several cellular responses (Figure 14.13). These responses include modifying protein synthesis and stimulating degradation of damaged proteins (Figure 14.13). If damage becomes too extreme to repair, the UPR can then stimulate programmed cell death (apoptosis; Figure 14.13).
Figure 14.13 An overview of the unfolded protein response (UPR), in which denatured proteins inside the lumen of the rough endoplasmic reticulum stimulate intracellular signalling pathways to shut down synthesis of most proteins, upregulate synthesis of chaperone proteins, initiate ER-associated degradation (ERAD) of damaged proteins, and (if needed) stimulate autophagy or apoptosis. [Will need to simplify and redraw. Image is from https://www.tocris.com/cell-biology/er-stress-upr, which is based on image is from https://www.nature.com/articles/nri2359 (available through NovaNet)]
Effects of UPR on protein synthesis
The UPR affects protein synthesis in two major ways. First, the UPR inactivates proteins that are important for protein translation. Therefore, few new proteins will be synthesized. This is important because under stress these new proteins would likely misfold and be non-functional. The cell should therefore direct its energies elsewhere. The second impact on protein synthesis by the UPR is the selective increase in synthesis of proteins involved in the cellular stress response. One major group of proteins that increases in synthesis during the UPR are molecular chaperones. As discussed in Chapter 14.3, these molecular chaperones can help refold or at least prevent aggregation of unfolded/misfolded proteins. Another group of proteins that are synthesized during the UPR as those involved in ERAD, which is discussed next!
Activation of ERAD
The endoplasmic reticulum-associated degradation (ERAD) process is important for ensuring that damaged proteins in the ER lumen are degraded by proteasomes (Figure 14.14). First, damaged proteins within the ER lumen are moved towards the ER membrane and transported across the ER membrane into the cytosol via a transmembrane transport protein. During transport, other proteins in the ER membrane catalyze ubiquitination of this damaged protein on the cytosolic side of the ER membrane. Once transport into the cytosol is complete, the protein is degraded by proteasomes as described in Chapter 14.3. The resulting free amino acids can be used to synthesize new proteins.
Figure 14.14 An overview of the ERAD (endoplasmic reticulum-associated degradation) of damaged proteins within the ER lumen by proteasomes in the cytosol. [will need to simplify/replace; image is from https://www.nature.com/articles/nrm2546 (available through NovaNet)]
Activation of autophagy and/or apoptosis
A second mechanism to degrade damaged proteins, along with other damaged cellular components, is autophagy. Thus, while ERAD is a good process for degrading proteins from the endoplasmic reticulum, proteins from other sources are more likely to be degraded by autophagy. This autophagy can be stimulated as part of the UPR, resulting in break down of proteins in lysosomes. The details of autophagic mechanisms are discussed in Chapter 14.3. As with proteasomal degradation, the resulting free amino acids can be used to synthesize new proteins. If protein denaturation in the ER lumen is persistent, the UPR can stimulate apoptosis – a regulated form of cell death. This is likely to occur only if protein damage is accumulating faster than the damage can be repaired. The mechanisms of apoptosis are discussed in Chapter 14.5.