Endoplasmic Reticulum Stress
Cell stress responses are crucial in deciding if a cell lives or dies, and so plays a role in many diseases where cells either die unnecessarily, such as in degenerative diseases, or grow out of control, such as in cancer.
Our researchers are particularly interested in a type of cell stress called Endoplasmic Reticulum (ER) stress, and its role in protecting cancer cells from dying when exposed to chemotherapy or other cancer treatments. In the cell, the ER is responsible for folding, processing and quality control of proteins that are destined to be secreted or inserted into the plasma membrane. When the cell experiences stress, (e.g., cancer cells under pressure to rapidly grow and divide) the ER becomes stressed as it is unable to cope with the load of proteins it has to fold. Unfolded proteins accumulate, triggering an adaptive response called the Unfolded Protein Response (UPR). The UPR activates a series of molecular pathways that attempt to clear the unfolded proteins and increase the capacity of the ER to fold proteins. If the stress is too great, the cell switches from survival mode to the activation of its own death.
ER stress is an evolutionary conserved process aimed at minimising damage to the cell, but which can ultimately trigger cell death if the damage is too great.
The molecular mechanisms involved in switching from a protective response to a death response are not yet completely understood, but are crucial to developing strategies to limit or avoid the consequences of ER stress. Understanding and exploiting the ER stress response provides the potential to tackle many ER stress-associated diseases, such as cancer.
We are one of the leading research centres worldwide investigating ER Stress and we are continuously discovering new complexes, proteins and signalling pathways involved in ER stress that have important implications for cancer.
Professor Afshin Samali is ranked 1st in the world in Endoplasmic Reticulum research and 2nd in the world in ER stress research (Google Scholar, 2016). As you would expect, we have made major contributions to this field of research.
A review of ‘Mediators of Endoplasmic Reticulum Stress-Induced Apoptosis’ by Apoptosis Research Centre Researchers Eva Szegezdi, Susan Logue, Adrienne Gorman and Afshin Samali (EMBO Reports, 2016) has been widely cited by researchers worldwide (1,300 cites).
Below are some other, recent examples of our advances in this research area:
For many years, cells were known to either die in a systematic, programmed way, known as ‘apoptosis’ or in a random, uncontrolled way, releasing cell death products into the extracellular space, known as ‘necrosis’. In the last 10 years, a new form of cell death called ‘necroptosis’ has been described. The process of necroptosis could be defined as a regulated form of necrosis. In 2015, Professor Afshin Samali’s group discovered that, in response to ER stress stimuli, L929 cells (a murine cell line used to study TNF-induced necroptosis) induced necroptosis instead of apoptosis (Saveljeva et al., Cell Death Dis. 2015). They also showed that ER stress-induced necroptosis is mediated by the TNF receptor, independent of the TNF ligand.
Our researchers have made a number of advances in understanding how the various different pathways or arms of the Unfolded Protein Response (UPR) works in response to ER stress.
A number of years ago, Professor Samali’s group demonstrated how chaperones in the cytosol physically interact with ER stress sensors to regulate the UPR. Specifically, they demonstrated that heat shock protein 72 can control the activity of the ER Stress sensor, IRE1 by directly binding to its cytosolic domain (Gupta et al., PLoS Biol., 2010). This binding enhances IRE1 signalling at the ER and inhibits ER-stress induced apoptosis.
More recently, Professor Afshin Samali and Dr Susan Logue became interested in a relatively unknown protein called Sestrin-2, when they discovered from a microarray experiment that it is regulated by ER stress. They further investigated Sestrin-2 and went on to discover the mechanism by which this new target is regulated by ER stress. They demonstrated for the first time that it is regulated by the ER stress sensor, IRE1 and they confirmed that it is also regulated by the ER stress sensor, PERK (Saveljeva et al., Oncotarget, 2016). Their research showed that that breast cancer cells ramp up production of Sestrin-2 in order to dampen the cell’s stress response and survive harsh conditions. From this research, we now know that Sestrin-2 is an important pro-survival factor in cancer, whose expression alleviates ER stress in order for cancer cells to survive
In 2016, Dr Adrienne Gorman’s group published the first comprehensive review of the Integrated Stress Response, an adaptive pathway activated in response to diverse stimuli and common to all eukaryotic cells (Pakos-Zebrucka et al., EMBO Rep. 2016). This pathway is activated to restore cellular homeostasis when the cell experiences stress. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α), which leads to a decrease in the cell’s protein production and the coordinated induction of selected genes that promote cellular recovery. Although the Integrated Stress Response is primarily a pro-survival programme, exposure to severe stress can drive signalling towards cell death. This review provides an extensive report on our current understanding of the Integrated Stress Response signalling and how it regulates cell fate under diverse types of stress.
Ongoing research at the Apoptosis Research Centre in the area of ER Stress includes:
- Investigating the role of IRE1, one of three major ER stress sensors, in breast cancer (Prof Afshin Samali’s group)
- Investigating how IRE1 controls cell death and survival and how it is regulated by heat shock proteins (Dr Adrienne Gorman’s group)
- Targeting IRE1 in pre-clinical models of breast cancer (Dr Susan Logue’s group)