mRNA unzipping spurs plant cells to fight infection

DURHAM, NC — From bacteria to plants to humans, life forms a chemical soup of proteins — life’s workhorse molecules — to adapt to stress or changing conditions inside their cells, when nutrients are scarce or when a pathogen strikes.

Now, researchers have identified a previously unknown molecular mechanism that helps explain how they do it.

A team led by Duke University is studying the spiral plant Arabidopsis thaliana was discovered Short pieces of folded RNA keep the levels of defense proteins low enough to keep plants from harming them under normal conditions. But when plants detect a pathogen, these folded RNA structures are unzipped, enabling plant cells to produce defense proteins to fight the infection.

The findings are not limited to plants, the authors noted on Sept. 6 publication In the journal Nature. They also found that these RNA structures have similar effects on protein production in human cells.

„It’s another tool in our toolbox” to control protein production, said the Duke biology professor Jinnian TongSenior author of the study.

Inside every cell in the body, millions of protein molecules perform the tasks of life: they are the cellular equivalent of bricks and beams, providing structure and support. They are the cell’s chemical messengers, sending and receiving signals. They are protectors, used in response to foreign invaders.

To make a protein, parts of the DNA blueprint packed into the cell’s nucleus are transcribed into messenger molecules called mRNA, which are the instructions for making proteins. These instructions are carried to the rest of the cell, where decoding devices called ribosomes translate the mRNA’s message to link chains of amino acids, the building blocks of protein.

Normally, until ribosomes find a special three-letter sequence along the mRNA molecule that says, „Start here to make a protein.”

But in the new study, Dong et al Yezi Xiang, a Ph.D. student in Tong’s lab, when an Arabidopsis seedling detects a potential pathogen, the plant’s ribosomes bypass the usual 'start’ signal for protein synthesis and start translating the mRNA further downstream, producing a completely different chain of amino acids — and thus a different protein — needed to fight the infection.

Tang and his team wanted to know: How do cells switch from one initiation site to another?

To better understand this rapid cellular decision-making, the researchers turned to a technique used when a plant detects an invader. shape-mapThis allows detection of changes in mRNA folding within cells.

Next to the typical 'green light’ that sets protein synthesis into motion, the researchers discovered short stretches of mRNA that fold back on themselves to form double-stranded „hairpin” structures.

Under normal conditions, these hairpins act as brakes, preventing ribosomes from making protective proteins whose instructions are further downstream.

But when Arabidopsis seedlings sense they are under attack, special enzymes called RNA helicases are produced that unwind the hairpins so that ribosomes can continue to scan along the mRNA molecule.

„If these stop signals are removed, the ribosomes don’t stop there, but go further downstream to translate protective proteins,” Dong said.

Although the team performed most of their experiments in Arabidopsis plants, similar RNA helicases and hairpin structures have been found in other organisms, from yeast to humans, suggesting that this mechanism of reprogramming protein synthesis may be widespread.

In follow-up experiments, the researchers used machine learning to come up with a lab-created mRNA hairpin design and insert it into human genomes. Synthetic hairpins also worked to alter protein production in human cells.

The team has filed for a provisional patent for the invention.

The findings could lead to new ways to make crops „resistant not only to pathogens, but also to environmental stresses such as heat, cold and drought,” says Dong.

In the future, Dong said, mRNA hairpins could be designed for gene editing to fight infections or treat diseases in people.

„The goal is to help cells produce the right amount of protein at the right time and in the right place,” Tong said. „This is a step toward that goal.”

This work was supported by grants from the US National Science Foundation (IOS-1645589 and IOS-2041378), the Howard Hughes Medical Institute, the State Key Research Development Program of China (2019YFA0110002), and the Natural Science Foundation of China (32125007 and 91940). ), and the US National Institutes of Health (R35-GM122532).

Citation: „Pervasive Downstream RNA Hairpins Dynamically Dictate Start-Codon Selection,” Yezi Xiang, Wenze Huang, Lianmei Tan, Tianyuan Chen, Yang He, Patrick S. Irving, Kevin M. Weeks, Qiangfeng Cliff Zhang. Ninature. 6, 2023. DOI: 10.1038/s41586-023-06500-y