Insight into Cellular Stress: Mechanisms Behind mRNA Sequestration Revealed

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The formation of stress granules hinges on a minuscule chemical alteration found on mRNAs, referred to as m6A. The findings are published in Nature Structural and Molecular Biology ().

mRNAs (messenger RNAs) are a type of ribonucleic acid (RNA) molecule that plays a crucial role in the process of protein synthesis in cells. m6A stands for N6-methyladenosine and refers to to a specific chemical modification that can occur on mRNA molecules. Researchers have increasingly recognized the importance of m6A modifications in various biological processes and their relevance to diseases like cancer and neurological disorders.

‘Scientists have shed light on how messenger RNAs (mRNAs) prompt cellular responses to stress. These discoveries may hold significance for conditions like Alzheimer's and ALS, where this mechanism could be overly active. #mRNA #stress’

When stressed by heat, toxins or other potentially damaging factors, cells gather many of their messenger RNAs (mRNAs), molecules that carry the instructions for making proteins, into droplet-like compartments called stress granules. These granules sequester affected mRNAs, preventing them from being translated into proteins. The resulting slowdown in protein production helps the cell conserve energy, declutter and focus on repairs.

"We were able to show that m6A has a primary role in driving mRNAs into these granules during cell stress," said study senior author Dr. Samie Jaffrey, the Greenberg-Starr Professor of Pharmacology at Weill Cornell Medicine.

The study's first author, Dr. Ryan Ries, was a Weill Cornell Graduate School of Medical Sciences doctoral student during the research.

Gaining Insight into the Formation of Stress Granules

Stress granules contain many different mRNAs from the cell, but not a random selection. Dr. Jaffrey and his team previously showed that mRNAs that are found in stress granules are often chemically tagged with a small cluster of atoms called a methyl group which attaches to adenosine, one of the mRNA building blocks. The resulting mRNA has regions that are enriched in N6-methyladenosine, or m6A. They also found that m6A-rich regions bind to YTHDF proteins-the more m6A an mRNA has, the more YTHDF proteins are present. The large amount of YTHDF proteins is needed to allow the m6A-mRNA-YTHDF complexes to accumulate into stress granules.

Dr. Jaffrey and others assumed that m6A wasn't the only factor directing mRNA into stress granules because longer mRNAs are also overrepresented. "We had thought that mRNA length was another factor, which is plausible since longer mRNAs have a tendency to stick to other mRNAs and form aggregates," Dr. Jaffrey said.

However, in this study, when the researchers engineered cells that couldn't form m6A and induced stress granule formation, they found that longer mRNAs weren't overrepresented in the granules anymore. Dr. Jaffrey concluded that the m6A in the long mRNAs, and not mRNA length per se, was the key factor making longer mRNAs disproportionately abundant in stress granules.

What Causes Longer mRNAs to Prevail in Stress Granules?

During protein production, mRNAs are assembled in the nucleus of a cell from smaller regions of RNA called exons. The researchers observed that m6A is added to mRNAs as soon as the mRNAs are made in the nucleus. They also discovered that exons that were unusually long strongly triggered m6A formation in the corresponding mRNA. These long exons tend to be in long mRNAs, which explained why long mRNAs have high levels of m6A, and therefore are more likely to join stress granules, compared to mRNAs that are composed of only short exons.

Why does it benefit a cell to sequester longer mRNAs during episodes of cell stress? Dr. Jaffrey and colleagues speculate that in the distant evolutionary past, longer mRNAs were more likely to be dysfunctional or even from viruses. The development of cellular pathways to direct m6A-mRNAs into stress granules may have originated as a way to lock up these suspect mRNAs and prevent them from making unsafe proteins-though that process now appears to have evolved into a broader stress-response function.

"Maybe the abnormal stress granules that are formed in neurodegenerative diseases such as Alzheimer's and ALS are driving those disease processes by chronically trapping beneficial m6A-containing mRNAs," Dr. Jaffrey said. "We hope to find out whether blocking that mRNA-trapping process will help reverse pathology in these neurons."

Reference:

1. m6A governs length-dependent enrichment of mRNAs in stress granules - (https:www.nature.com/articles/s41594-023-01089-2)

Source: Eurekalert