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SVI researchers discover gene’s ‘security guard’ role in cells

Posted: 07th October 2015

New research resulting from a collaboration between groups at St Vincent’s Institute in Melbourne and researchers in the USA and Germany, has shown that a specific protein in the cell called ADAR1 adds a distinct chemical signal to the cell’s own RNA –a ‘me’ signal—so that the cell can recognise the difference between its own RNA (self) and foreign RNA (non-self). When ADAR1 function is disabled, the cell's own RNA causes the cell to behave as if it has been infected by a virus.

The findings were published today in the prestigious American Association for the Advancement of Science (AAAS) Journal Science.

“The cell has a warning system that senses foreign RNA, such as from a virus, and activates an immune response to combat the infection. This system is not supposed to detect the cell’s own RNA,” said lead researcher Dr Carl Walkley, Joint Head, Stem Cell Regulation Unit at SVI. “In essence, ADAR1 works like a security guard; the guard issues security passes for people who work in the building and authorizes their presence. When unauthorized people in the building are recognized by the alarm system, which would otherwise not be able to tell the difference, it sets off an alarm.”

Dr Walkley further explains that until their studies, it was not clear whether ADAR1 also had other functions.

“To hone in on its specific function, we mutated a key function of ADAR1. When we did so, we found that the cell reacted as if it was infected by a virus even when there was no infection present. We believe this is because the cells alarm system, in this case a protein called MDA5, was “seeing” some of its own RNA as foreign.”  By doing this, the researchers were able to confirm the specific role of ADAR1.

“Imagine the security guard couldn’t see the passes, and so everyone in the building—even those who are allowed to be there— could be suspected of being unauthorized, causing the guard to set off the alarm unnecessarily or for the wrong reasons.”

This discovery means researchers will now be able to better understand how cells are able to tell the difference between their own RNA and foreign RNA such as that from a virus. It should also improve our understanding of what happens in patients with mutations in ADAR1.

Mutations in the ADAR1 gene have been linked to a rare autoimmune disorder called Aicardi-Goutières Syndrome. The early-onset disease affects the brain and skin and those affected can have significant intellectual and physical problems. The syndrome is extremely rare and can be caused by mutations in a number of genes, including ADAR1.

The research was funded by the Leukaemia Foundation Australia and the Federal Government’s National Health and Medical Research Council.

*Group Image (l to r): PhD student Brian Liddicoat, Dr Alistair Chalk, Dr Carl Walkley (Joint Head) - SVI Stem Cell Regulation Unit

For more information please see: Stem cell regulation