Cells use backup mechanism to recognize potential invaders when usual RNA editing process fails, study finds microbiologystudy

Our cells need to be able to recognize potential invaders as a threat, the key function of the body’s innate immune system. Sometimes this process fails, causing the body to react to its own cells, leading to autoinflammatory disease. New research has identified a critical fall-back mechanism used by the cells when the usual RNA editing process is switched off.

Professor Carl Walkley heads the RNA Biology and Innate Immune Sensing Research Group at Hudson Institute of Medical Research, and their latest study, published in Science Immunology, sheds new light on these crucial processes.

He explained that cells must be able to determine between their own RNA (“self”) and foreign RNA (“non-self”) that may be a threat, such as a virus.

“We know cells use the protein ADAR1 and a process called A-to-I RNA editing as an important way to mark ‘self’ from ‘non-self’ RNA. We have now found a new pathway allowing cells to tolerate losing ADAR1 mediated A-to-I editing, preventing immune reactions from being triggered,” he said.

RNA editing identifies invaders

Working with collaborators from the Peter MacCallum Cancer Center, Victorian Comprehensive Cancer Center, Spain’s Universidade de Santiago de Compostela, and Stanford University, U.S., the team expanded the understanding of how cells can adapt to changes in A-to-I editing and also identified new ways RNA can be handled in the cell.

Among the benefits of this new understanding is a potential application in Aicardi-Goutieres Syndrome (AGS), a rare inherited disease affecting the immune system and associated with elevated type I interferon, for which there are currently no effective treatments.

Prof Walkley said that ADAR1 mutations are one of the causes of AGS. “Our work identifies previously unknown pathways that can allow cells to tolerate a loss of ADAR1 activity. These new pathways or proteins may be new targets to explore as potential treatments for this disease.”

The multinational research also developed a new cell line model to study loss of ADAR1 functions, as well as isolating key regulators of the autoinflammatory response to unedited self dsRNA and identifying a new pathway regulating the cellular response to immunogenic self dsRNA.

Innate immunity explained

The innate immune system is your body’s first line of defense against harmful invaders like bacteria and viruses. It responds quickly and doesn’t need prior exposure to recognize threats.

It incorporates physical barriers, such as skin and mucous, cells like macrophages and neutrophils that “eat” germs, and chemical signals like cytokines that trigger inflammation. It also includes specialized proteins in the cell cytoplasm that sense and act to destroy invaders.

The innate immune system acts as a rapid response team, buying time for the adaptive immune system to kick in if needed.

A-to-I RNA editing is a process that directly changes the sequence and structure of RNA. It occurs on the cell’s own RNA and we now appreciate that this is an important way that cells can recognize potential RNA threats.