Cells Use mRNA to Fight Disease and Stress

Scientists study the role of mRNA and protein synthesis in overcoming infections. This finding could lead to improved crops and medical treatments.

By Rachil Koumproglou

DNA contains the code of life. Our genes inform our cells how to make proteins, those biological molecules that are important for all functions of life. From genes to proteins, an intermediary molecule called the messenger RNA, or mRNA, copies the information of the DNA and carries it to the sites of protein production. 

Now, a study led by Dr. Xinnian Dong from the biology department of Duke University (Durham, NC, USA) has shown that mRNA helps organisms to survive in harsh environments by modifying its structure and affecting the production of proteins. This discovery opens the way to the manipulation of mRNA molecules to cure diseases or create crops with resistance to heat or water stress.

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From genes to protein synthesis

Before we can understand the role of mRNA in supporting protein synthesis, let’s take a look at proteins generally. Proteins have multiple effects on the phenomena of life. Some are enzymes that make chemical reactions happen faster in living organisms; some are the building blocks of cells and tissues; and others communicate signals between cells or from the environment to the organism to enable growth or survival in adverse conditions. 

Every protein is a big molecule composed of smaller units called amino acids; and each type of protein has a unique sequence of amino acids. The instructions for producing a protein exist in the sequence of nucleotides of a single gene. This process is called “translation”—that is, the sequence of nucleotides is translated to the sequence of amino acids. 

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A general rule applies for decodifying the DNA sequence: three specific nucleotides create a group, known as a codon, that corresponds to an amino acid. The first amino acid in any protein chain (which is almost always a methionine) is specified by the AUG nucleotide sequence, known as the starting codon or mAUG. 

Protein synthesis occurs in microscopic structures, called ribosomes, within the cells. The mRNA arrives at the ribosomes carrying the genetic information packed in a single-stranded chain of nucleotides. In the ribosome, an assembly of enzymes—the translation initiation complex—starts scanning the mRNA chain to find the starting codon. Once it is found, the amino acids arrive and are joined together to create the new protein, following the “manual” printed in the nucleotide sequence of the mRNA.

Folding and unfolding of mRNA molecules to fight disease

Previous studies have shown that changes in the environment may stop or promote the translation of the mRNA into certain proteins. However, this is the first time that a study obtained a panorama of the translation machinery under conditions of infection, using state-of-the-art sequencing methods and machine learning algorithms. They selected to work with Arabidopsis, a small weedy plant that is used as a reference species for biological studies in plants. 

To simulate an adverse environment, they treated Arabidopsis plants with a protein emitting a signal that plants are infected and need to activate their immune system. Next they collected, analyzed, and sequenced thousands of translated mRNA molecules from treated and untreated plants. They found that, in the treated plants, there are more mRNAs that specify proteins involved in the immune system. The sequencing showed that these mRNAs contained several starting AUG codons before the main starting codon—the one that specifies the first amino acid of the immune-related protein. 

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The scientists made a breakthrough with their next results. They showed that, in the untreated plants (those with no simulated infection), the discovered starting codons are neighbored by small stretches of the mRNA chain that fold and create loops. These loops, also called hairpins, work as “brakes” that slow down the ribosome device while it moves along the mRNA. They also keep it away from the main starting codon. At the end, the ribosome stays trapped at this site and starts producing a non-functional protein from the wrong starting codon.

Controlling protein production at the molecular level

The discovery that plants stop producing immune-related proteins under no-infection conditions shows the ways in which nature has equipped organisms to use their energy prudently. If these proteins were present, the plants would need to direct all their energy to defense instead of growth and reproduction. But what happens if a plant is infected? How will it start producing the proteins that it needs to protect itself? 

To understand what happens, the scientists challenged the plant with an infection signal and discovered that an enzyme called helicase arrived at the site where the ribosome complex had previously stopped. There, it starts destroying the nearby hairpin and releases the trapped ribosome complex. This starts its journey along the mRNA molecule again. Then when it finds the mAUG, it produces the correct defense protein. 

Helicases—the enzymes that destroy the hairpins—exist in all living organisms, including humans. This study’s evidence about helicases was so compelling that the scientists decided to test if the discovered mechanism of controlling protein production is universal. If it is, it will open the way to new therapy treatments of human diseases. To prove it, they created mRNA fragments in the laboratory and introduced them to human cells. They discovered that the same process controls the production of proteins under certain conditions. 

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Recognizing the value of their discovery, the researchers have filed for a patent. In future, synthetic mRNA hairpins can be used to turn on or off the production of particular proteins and help humans to avoid a disease or to fight an infection. Likewise, they can make crops more resistant to stress-related conditions like high temperatures or lack of water. 

This study was published in the peer-reviewed journal Nature.

Reference

Xiang, Y., Huang, W., Tan, L., Chen, T., He., Y., Irving, P. S., Weeks, K. M., Zhang, Q. C., & Dong, X. (2023). Pervasive downstream RNA hairpins dynamically dictate start-codon selection. Nature, 621, 423–430. https://doi.org/10.1038/s41586-023-06500-y