Stressed Cells Sequester Protein-Forming mRNAs, Say Scientists

Weill Cornell Medicine researchers have discovered one of the critical ways that cells respond to stress. The findings may potentially be relevant to Alzheimer’s disease, ALS, and other disorders in which this mechanism is overactive. When cells are stressed by heat, toxins, or other potentially harmful conditions, they aggregate many of their messenger RNAs (mRNAs), molecules that convey protein-making instructions, into droplet-like compartments known as stress granules. These granules bind to impacted mRNAs and prevent them from being translated into proteins. The consequent decrease in protein creation aids the cell in conserving energy, decluttering, and focusing on repairs.

The study, published on September 14 in Nature Structural and Molecular Biology, demonstrated that m6A, a small chemical change on mRNAs, is essential for the creation of stress granules.

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

During the research, Dr. Ryan Ries was a PhD student at Weill Cornell Graduate School of Medical Sciences.

Understanding the Formation of Stress Granules

Stress granules contain a wide range of messenger RNAs from the cell, but not at random. Dr. Jaffrey and colleagues previously demonstrated that mRNAs discovered in stress granules are frequently chemically tagged with a small cluster of atoms known as a methyl group that links to adenosine, one of the mRNA building components. The resultant mRNA contains N6-methyladenosine, or m6A-enriched sequences. They also discovered that m6A-rich areas bind to YTHDF proteins, and that the more m6A an mRNA has, the more YTHDF proteins it contains. A significant number of YTHDF proteins are required for the m6A-mRNA-YTHDF complexes to collect 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.

In this study, however, when the researchers produced cells that couldn’t make m6A and stimulated stress granule production, they discovered that longer mRNAs were no longer overrepresented in the granules. Dr. Jaffrey found that the m6A in long mRNAs, rather than mRNA length per se, was the essential determinant in the disproportionate abundance of longer messenger RNAs in stress granules.

Why do longer mRNAs outnumber shorter mRNAs in stress granules?

mRNAs are assembled in the nucleus of a cell during protein creation from smaller sections of RNA known as exons. The scientists discovered that m6A is added to messenger RNAs as soon as they are formed in the nucleus. They also discovered that abnormally long exons greatly induced m6A production in the matching mRNA. Long exons are more common in long mRNAs, which explains why long mRNAs contain higher quantities of m6A and are thus more likely to join stress granules than short exon mRNAs.

Why does a cell profit from sequestering longer messenger RNAs during cell stress? Dr. Jaffrey and colleagues hypothesize that in the distant past, longer mRNAs were more likely to be defective or even viral. The evolution of cellular pathways that guide m6A-mRNAs into stress granules may have started as a mechanism to lock up these questionable messenger RNAs and prevent them from generating dangerous proteins, but it now appears to have developed into a broader stress-response role.

While the new discovery adds to our understanding of the basic biology underpinning m6A and stress granule development, it may also have implications for neurodegenerative illnesses.

“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.”

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