Molecular proofreading mistakes drive rare autoimmune diseases

Scripps researchers find that RIG-I mutations trigger autoimmunity by failing to distinguish between self and viral RNA

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JUPITER, FL—A team from Scripps Research has found a molecular cause of a group of rare autoimmune disorders in which the immune system attacks the body’s own healthy cells, detailed in the study, “HDX-MS reveals dysregulated checkpoints that compromise discrimination against self RNA during RIG-I mediated autoimmunity.”
The discovery, published today in Nature Communications, improves understanding of a protein’s role in several autoimmune disorders, including Singleton–Merten syndrome (SMS), Aicardi-Goutières syndrome, familial chilblain lupus, proteasome associated autoinflammatory syndromes and many others which involve improper stimulation of interferon, noted Patrick Griffin, Ph.D., professor and co-chair of the Department of Molecular Medicine at Scripps Research’s Florida campus.
Interferon is a key component of our frontline defense against pathogens, interfering with viruses’ ability to make copies of themselves. The immune system relies on a gene called RIG-I, short for retinoic acid inducible gene-I, to signal for the release of interferon whenever certain viral markers are encountered. RIG-I determines if the markers are of foreign origin or are from its own body. The team demonstrated precisely how mistakes in a molecular proofreading system can lead to confusion and generate out-of-control interferon signaling, leading to the development of autoimmune disease.
“This dysregulated molecular mechanism of RIG-I mediated RNA proofreading that we identified may help us understand and treat SMS and other autoimmune disorders,” said Jie Zheng, Ph.D., a postdoctoral associate and the first author and co-corresponding author of the study.
That is true for SMS, which is so rare that only a few cases have been described in the medical literature. Patients develop serious bone, heart, muscle and skin problems starting in early childhood, largely due to chronic inflammation from an overactive immune system.  The scientists’ aim was to understand how two RIG-I mutations linked to SMS end up triggering the autoimmunity.
Most viruses have genes made of ribonucleic acid, or RNA, a close chemical cousin of DNA.  RIG-I works as an early-warning detector of viral RNA, capable of triggering a broad antiviral immune response, including interferon release. The scientists showed that mutations in RIG-I cause the sensor protein to activate even when it encounters non-viral self RNA.
RIG-I is a big protein with flexible elements, and is hard to study with standard techniques. But Griffin has helped pioneer the use of an advanced technology called hydrogen-deuterium exchange mass spectrometry (HDX-MS), which enables scientists to analyze the structures and dynamics of proteins such as RIG-I. For the study, he and his team applied HDX-MS to normal and mutant RIG-I, and discovered how these mutations cause a failure of discrimination between self and viral RNA.
Scientists have known that RIG-I has a particular segment that it keeps mostly covered and concealed. When RIG-I encounters and recognizes viral RNA, this segment is supposed to briefly swing open and thus become available for binding to another protein called MAVS, an event that triggers the immune response. Griffin and colleagues found that the two SMS-linked mutations, in subtly different ways, cause this key segment of RIG-I to become stuck open — making it much more likely to bind to MAVS and trigger an immune response.
The Scripps researchers are now using their data to try to find a way to target mutant RIG-I, to block its inappropriate signaling to MAVS and thus alleviate the autoimmunity it causes. According to Griffin, this new, detailed understanding of RIG-I’s dysfunction may not only provide insights into the origins of more common autoimmune disorders, but also clarify how RIG-I works normally to detect viruses, a discovery that may enable development of new antiviral drugs.

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