The Integrated Stress Response (ISR) is a conserved signaling pathway across species and an important area of focus for Calico because of its possible link to many age-related diseases and its potential as a target for new drug development. Calico is currently developing an ISR inhibitor, Fosigotifator (ABBV-CLS-7262), which is being tested in the clinic as a potential treatment for two neurodegenerative diseases.
To gain a deeper understanding of how the ISR controls cell states, the Calico team used a highly specific and tunable cellular model to disentangle the effects of the ISR from other processes that are engaged when cells encounter stress or damage that disrupts them. In a new paper published in Nature Communications, they describe how the ISR uniquely rewires cellular metabolism and how it broadly remodels the lipid content of the cell.
“Disease and aging disrupt the body’s biological balance, so it’s important to keep our cells, which are responsible for maintaining that balance, functioning properly,” said Lauren LeBon, Senior Scientist and co-author of the study. “If we can understand the function of stress responses in normal cells and how that function can decline as homeostasis is lost, it will tell us how stress response pathways might be contributing to disease and aging.”
A key discovery was the suppression of a process known as the tricarboxylic acid (TCA) cycle which is a series of reactions that are essential for creating energy via cellular respiration. The researchers found that when the ISR is turned on even at low levels, carbon is redirected from mitochondria to make amino acids and glutathione, a key antioxidant that protects cells. This shows how the ISR may help cells adapt to mitochondrial dysfunction or starvation, two common triggers of the pathway, by rewiring their metabolism.
Using a synthetic tool they also showed that activation of the ISR can lead to the formation of droplets that store fats, also known as lipids. “Just turning on the ISR pathway is enough to generate these lipid droplets,” says Katherine Labbé, Senior Scientist and co-author of the paper. “This is interesting because lipid droplets have been linked to neurodegenerative diseases.” The team also found that the enzymes DGAT1 and DGAT2, which mediate the same conversion step to generate triglycerides, play different and critical roles in forming these droplets and helping cells survive. They showed that just blocking DGAT2 further activated the stress response, suggesting that this enzyme normally helps buffer stress through a yet unknown mechanism.
While further research will continue to reveal when the ISR helps or harms cell health, this study represents a meaningful step forward in characterizing this ubiquitous pathway and advancing our understanding of how it temporally fine tunes gene expression, metabolism, and fat trafficking or storage in cells.
Read the full article, “Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis,” in Nature Communications.
The image shows that an activated integrated stress response (ISR) leads to the accumulation of stress granules (magenta) and lipid droplets (green) in U2OS cells (nucleus in blue), which are used to study metabolic function.