Scientists have revealed a key mechanism that is involved in controlling the cell’s response to stress, according to a study published today in eLife. The discovery provides new insights into a stress-response mechanism called the unfolded protein response (UPR), helping researchers understand the processes that protect cells, boost immunity, and extend lifespan.
“We had previously identified genes that are important for the activation of the mitochondrial stress response,” explains lead author Kaiyu Gao, graduate student at Peking University. “Among these was the ULP-4 gene, which is an enzyme that removes a molecule called SUMO from proteins, dramatically affecting their function. In this study, we set out to see whether the ULP-4 enzyme was necessary for the stress response and whether it influenced this response by removing SUMO groups.”
The team first blocked the activity of the ULP-4 gene in worms and noticed that it prevented the stress response in mitochondria but not other parts of the cell. When they restored high levels of the ULP-4 molecule into the ULP-4-deficient worms, they found that the animals were again able to activate the mitochondrial stress response, suggesting that ULP-4 is necessary for mitochondrial UPR.
Next, the team conducted protein-binding experiments in yeast cells, in which they identified two molecules that interact with ULP-4 called DVE-1 and ATFS-1. Both molecules have specific sites where a SUMO group could be added, so the next question was whether ULP-4 was involved in removing these groups and whether this affected mitochondrial UPR. The team found that ULP-4 does, in fact, remove the SUMO group from DVE-1 and ATFS-1, both in yeast cells and in worms.
Finally, the researchers looked at how ULP-4 affects the resilience and lifespan of the worms. They found that worms lacking ULP-4 had a suppressed immune response and impaired survival following infection with Pseudomonas bacteria. And under stressed conditions, a deficiency in ULP-4 (or preventing the addition of SUMO groups by mutating DVE-1 or ATFS-1) dramatically reduced lifespan.