Scientists Discover ‘Gene Remixing’ Helps Cells Fight Infection
U of T researchers have discovered that cells change their genetic instructions to defend against infections including Salmonella, Shigella and Listeria. It’s a discovery that may help scientists develop new therapeutics against these bacteria.
“Genetic information in our cells can be reshuffled or ‘spliced’ to generate more diversity, but until now, scientists didn’t fully understand how this phenomenon could help fight off infection or respond to metabolic stress,” said Stephen Girardin a professor in the Faculty of Medicine’s Department of Laboratory Medicine and Pathobiology. “We’ve found that when infected or stressed, cells rapidly adjust the machinery that controls this genetic remixing.”
Girardin’s team studied a process called alternative splicing and how this routine cellular process changes during times of stress. Similar to remixing a song or re-editing a movie by copy and pasting different clips, alternative splicing allows the RNA — the molecules that translate our genetic material into proteins — to be rearranged in different ways. During alternative splicing, parts of the RNA are cut with “scissors” and pasted together to make new proteins. These new proteins can then carry out all of their necessary functions.
The researchers found that when a cell is dealing with an infection it sends these “scissors” into storage, also known as U bodies. By doing this, the cell changes its normal cutting and pasting process and the RNA is then used to create different proteins that respond to the infection.
Girardin’s research, led by graduate student Jessica Tsalikis, used human cells to reveal the importance of this “gene remixing” and their results were recently published in the Journal of Biological Chemistry.
“We think that when a cell is faced with an infection agent like Salmonella, the cell adapts by reading its DNA in a new way and starts producing different proteins,” said Tsalikis. “By understanding this process, we’re furthering our knowledge of basic human cell biology.”
The team’s findings may also help researchers understand a genetic neurodegenerative disease called spinal muscular atrophy. This disease leads to muscle wasting and is the most common genetic cause of infant death.
“Patients with spinal muscular atrophy don’t have the switch that moves the cell’s ‘scissors’ into storage, and their RNA is likely not spliced like it should be,” said Tsalikis. “As a result, we think that these cells have trouble coping with cellular stresses like infection and this makes the disease much worse.”
Next, the researchers will identify the new proteins that cells make when faced with stress. By identifying these proteins, they hope to add to the overall understanding of how genes are regulated during infection and starvation, and to potentially reveal new targets for therapeutics.
“Our study provides a novel understanding of how cells respond to stress and infection by linking these events to a fundamental cellular process,” said Girardin. “We’ve provided further evidence that metabolic stress is a major hallmark of bacterial infection, which is a novel paradigm that we are actively studying in my laboratory. We’re excited by the new perspectives in bacterial pathogenesis and spinal muscular atrophy that our work has generated, and we’re now working at identifying how our results could translate into novel therapeutics.”
