Research Story Tip: Cells under Stress Get Into Molecular ‘Traffic Jams,’ Triggering a Suicide Pathway
When cells experience a high level of stress — for example, when they are exposed to too much UV light — ribosomes inside the cell collide and get into traffic jams. Now, Johns Hopkins scientists have found a protein that recognizes this traffic problem and pushes the cell down a path toward cell suicide.
Molecular understanding of this pathway could lead to ways to control its outcome. A report of the research was published June 30, 2020, in the journal Cell.
Molecular biologist Rachel Green, Ph.D., and her team have long been studying how cells recognize problems within their coding information and how this recognition relies on cellular structure called the ribosome. These problems can arise from errors encoded in the genome or from environmental damage to the cell.
The ribosome travels along a piece of genetic material called messenger RNA (mRNA). The ribosome’s job is to decode the mRNA to provide a set of instructions for making a protein. When cell stress increases, and mRNAs are damaged, ribosomes can’t travel down the mRNA highway, and they tend to collide with each other like molecular bumper cars. Since these ribosomes fail to reach the end of the mRNA, they produce incomplete proteins.
“Incomplete proteins aggregate and cause diseases,” says Green, a Bloomberg Distinguished Professor of molecular biology and genetics at the Johns Hopkins University School of Medicine and Howard Hughes Medical Institute investigator. “The cell needs to stop incomplete proteins from being produced and aggregating.”
When ribosome collisions aren’t too abundant, cells can often recover. They initiate a pathway called the integrated stress response, which keeps them from dying. However, if the collisions are causing a major traffic headache, cells trigger the ribotoxic stress response, a pathway to cell suicide.
Green and her team aimed to find out how cells assess traffic conditions and spot these ribosomal collisions. So, they added an antibiotic that blocks ribosome movement to mammalian cells cultured in the laboratory.
The scientists found no problems with the traffic flow of ribosomes in untreated cells. With a high dose of the antibiotic, they found that ribosomes simply stopped moving all together. However, when the scientists treated the cells with an intermediate dose of the antibiotic, they saw widespread ribosome collisions in the cell, and to their surprise, activation of proteins involved in both the life-promoting integrated stress response and the death-promoting ribotoxic stress response.
In collaboration with her colleague, Johns Hopkins scientist Sergi Regot, Ph.D., Green identified a critical protein, called ZAK, which is part of a family of proteins called MAP3K. ZAK binds to colliding ribosomes and is itself activated.
Her team is planning studies to determine precisely where ZAK binds to ribosomes by using a cryoelectron microscope to create a 3D rendering of its structure. Green also aims to learn how different cell types may be more or less vulnerable to ribosome collisions.Green says an exciting potential outcome of the research is that the ZAK-mediated molecular pathway could be targeted with drugs to alter cell fate when they are under stress in health and disease.