'Traffic Jams,' Triggering a Suicide Pathway 5 August 2020, by Vanessa Wasta, M.B.A

Cells under stress get into molecular 'traffic jams,' triggering a suicide pathway 5 August 2020, by Vanessa Wasta, M.b.a.

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." A model of a human ribosome. Credit: National Institutes of Health 3D Print Exchange 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 When cells experience a high level of stress—for major traffic headache, cells trigger the ribotoxic example, when they are exposed to too much UV stress response, a pathway to cell suicide. light—ribosomes inside the cell collide and get into traffic jams. Now, Johns Hopkins scientists have Green and her team aimed to find out how cells found a protein that recognizes this traffic problem assess traffic conditions and spot these ribosomal and pushes the cell down a path toward cell collisions. So, they added an antibiotic that blocks suicide. ribosome movement to mammalian cells cultured in the laboratory. Molecular understanding of this pathway could lead to ways to control its outcome. A report of the The scientists found no problems with the traffic research was published June 30, 2020, in the flow of ribosomes in untreated cells. With a high journal Cell. dose of the antibiotic, they found that ribosomes simply stopped moving all together. However, when Molecular biologist Rachel Green, Ph.D., and her the scientists treated the cells with an intermediate team have long been studying how cells recognize dose of the antibiotic, they saw widespread problems within their coding information and how ribosome collisions in the cell, and to their surprise, this recognition relies on cellular structure called activation of proteins involved in both the life- the ribosome. These problems can arise from promoting integrated stress response and the death- errors encoded in the genome or from promoting ribotoxic stress response. environmental damage to the cell. In collaboration with her colleague, Johns Hopkins The ribosome travels along a piece of genetic scientist Sergi Regot, Ph.D., Green identified a material called messenger RNA (mRNA). The critical protein, called ZAK, which is part of a family ribosome's job is to decode the mRNA to provide a of proteins called MAP3K. ZAK binds to colliding set of instructions for making a protein. When cell ribosomes and is itself activated. stress increases, and mRNAs are damaged,

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Her team is planning studies to determine precisely where ZAK binds to ribosomes by using a cryoelectron microscope to create a 3-D 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.

More information: Colin Chih-Chien Wu et al. Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate, Cell (2020). DOI: 10.1016/j.cell.2020.06.006

Provided by Johns Hopkins University APA citation: Cells under stress get into molecular 'traffic jams,' triggering a suicide pathway (2020, August 5) retrieved 29 September 2021 from https://phys.org/news/2020-08-cells-stress-molecular-traffic- triggering.html

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