New Study Sheds Light on How Cells Respond to Stress

Biochemists at the University of Massachusetts Amherst have found that a damage-containment system in stressed bacteria can become overrun and blocked, but that this leads to cells responding by turning on very different pathways to make sure that normal growth continues.

Peter Chien, senior author on a paper published in Molecular Cell earlier this week, says that because all cells must maintain normal growth even during stressful conditions and all cells contain clean-up proteases that degrade used proteins and other waste, similar regulation may be at work in other biological responses. "Cancer cells also are constantly growing under protein stress conditions, so understanding how cells in general take advantage of protease competition to respond to stress leads to tempting speculations that we can inhibit similar pathways to block uncontrolled growth," he adds.

In bacteria, a protease known as Lon destroys damaged proteins to protect cells from their toxic consequences and degrades normal signaling proteins, as well. Stress that is toxic to proteins—causing misfolding, for example—prompts the bacteria not only to try to keep removing these damaged proteins, but to maintain processes like replicating DNA for normal growth. Zeinert studied the Lon protease and pathways it uses during cell stress, such as antibiotic attacks or extreme heat, to accomplish this.

In their new paper, the authors show that when bacteria are stressed, the increase in damaged proteins ends up temporarily swamping the Lon protease. This results in stabilization of signaling proteins that would normally be degraded by Lon, which sets off a cascade of responses, Chien explains.

"The misfolded proteins are canaries in the coal mines. When they build up so much that Lon is now blocked, the cells respond by turning on pathways needed to ensure growth." In particular, the cells increase the amount of deoxynucleotides—the 'DN' of DNA—building blocks that are needed for DNA replication."