Monitoring ribosome collisions

Significance 

Ribosomes are the machines in the cell that use instructions from mRNA to synthesize functional proteins. There are hundreds of thousands of ribosomes in each cell, and they mostly process their instructions faithfully. But sometimes ribosomes get stuck or stall on roadblocks along defective mRNA molecules.

New research from Washington University in St. Louis shows that cells monitor for ribosome collisions to determine the severity of the problem and how best to respond when things start to go awry. The research from the laboratory of Professor Hani Zaher   published in the journal Molecular Cell.

The cell has two methods of stress response that are triggered by this very same signal of ribosomes running into each other. However, the quality control mechanism of ribosome rescue and mRNA degradation responds more swiftly to resolve the problems and to prevent premature activation of the integrated stress response. Only after cells have exhausted the capacity of the quality control system do they move to shut down the entire translation system by activating the stress response.

The authors described the dynamic within the system that the cell can use to evaluate the level of stress from local, individual events, to events that require shutdown of the entire translation machinery. They discovered that cells are using ribosomes like sensors to alert them about changes in their environment. The scientists used drugs and genetic manipulations to alter ribosome speed and density, providing compelling evidence that both major kinds of stress response are activated in response to ribosome collisions.

When ribosomes are evenly distributed, rarely running into each other, cells know that conditions are good. When some ribosomes run into each other, cells recognize that there are problems and call on quality control factors to resolve the collisions. When many ribosomes are colliding with each other, cells go on high alert and shut things down. There’s a communication between these two pathways and the reason for that is that, even though the integrated stress response is a pro-survival pathway, it comes at a cost of shutting the cell down. You don’t want to activate it prematurely, unless you’re certain that there is a problem.

The researchers made their observations using a yeast model system, but the findings are applicable to mammal cells, too, they said. In humans, dysregulation of integrated stress response signaling has been linked to diseases including diabetes, cancer and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.

Monitoring ribosome collisions - Medicine Innovates
FIGURE: A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself.

About the author

Hani Zaher

Associate Professor of Biology
Program Director, Plant & Microbial Biosciences

Hani Zaher’s laboratory is interested in the functional role of RNA during the process of translation. Their long-term goal is to investigate the mechanism of ribosome function and to understand how other cellular factors and alterations to the RNA modulate its function.

Organismal growth and viability is dependent on the faithful decoding of genomic information into functional protein sequences. The overall fidelity of protein synthesis appears to be limited by the action of the ribosome, which is the biological machine responsible for the decoding of the messenger RNA into protein in all domains of life. In addition to careful substrate selection, the ribosome retrospectively monitors the quality of the just completed step by examining the tRNA-mRNA interaction in the P site to prematurely terminate protein synthesis if mistakes are detected. This latter retrospective editing mechanism depends on the class II release factor 3 (RF3). The long-term goal of Professor Zaher’s laboratory is to expand our understanding of the mechanisms that govern translational fidelity, and their impact on cellular fitness and codon evolution.

His immediate goal is to find out how the signal is communicated from a perturbed mRNA-tRNA interaction in the P site to the A site. He is also interested in how the activity of release factors is modulated on sense codons in the presence of a perturbed mRNA-tRNA interaction, and the structural cues that are responsible for this activity. These related goals are built around pre-steady state kinetics approaches in the context of mutated translation components, and low-resolution structural probing techniques. On a different front, Dr. Zaher’s lab explores the effects of translational fidelity on the overall gene expression and regulation at the elongation step through the use of proteomic, genomic and bioinformatic tools.

By discovering specific protein products that are potentially regulated by premature termination, key information about gene regulation and its relation to codon bias rules is likely to be delineated. Finally, his lab plans to characterize the editing mechanism in eukaryotes. Preliminary data indicate that the mechanism involves novel factors that are yet to be identified. He plans to take unbiased approaches to identify these factors and characterize them in vivo as well as in an in vitro reconstituted system.

Reference

Liewei L.Yan, Hani S.Zaher. Ribosome quality control antagonizes the activation of the integrated stress response on colliding ribosomes. Molecular Cell, Volume 81, Issue 3, 2021, Pages 614-628.e

Go To Molecular Cell

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