How an RNA Molecule in the Kidneys Triggers a Deadly Disease

Researchers from the University of Bonn have discovered that a small naturally occurring RNA molecule activates a mutated immune receptor, triggering a chain reaction. The scientists explained how a single-point mutation in the immune receptor RIG-I turns the body’s defense system into a self-destructive force, leading to severe autoimmune diseases that affect specific organs. The study results were published in Science Immunology.

RIG-I is an important sensor of the innate immune system that recognizes viral RNA and activates antiviral defense, reports Nauchnaya Rossiya (“Scientific Russia”). However, certain genetic changes, known as mutations, can make RIG-I hypersensitive, causing the immune receptor to mistakenly identify the body’s own RNA as viral.

The research team found that mice carrying the RIG-I E373A mutation, which is also found in patients, spontaneously developed lupus-like nephritis — a severe and often fatal kidney inflammation. Unlike classical lupus, where inflammation is caused by immune complex deposition, in these mice the disease resulted from direct kidney inflammation triggered by the mutated RIG-I.

Further investigation revealed that a short non-coding RNA known as Y-RNA, which is produced in large quantities in the kidneys, directly binds to the mutated RIG-I and causes its abnormal activation.

“We discovered that Y-RNA acts as a false alarm signal for the mutated RIG-I receptor, particularly in kidney cells,” said study author Professor Hiroki Kato. “This local immune malfunction causes strong inflammation resembling human lupus nephritis.”

“Using advanced molecular and structural analysis techniques, we were able to show that the mutant protein RIG-I-E373A binds to Y-RNA in an unusual way, leading to receptor activation even without viral infection,” said Saya Sato, the study’s first author. “This abnormal activation causes kidney cells to produce large amounts of interferons and chemokines, which attract immune cells and trigger inflammation.”

The researchers also identified a potential therapeutic target: blocking the CCR2 signaling pathway, which attracts monocytes (a type of white blood cell), significantly reduced kidney inflammation in the test mice.

Mutations in the RIG-I gene are associated with rare hereditary diseases such as Singleton–Merten syndrome and systemic lupus erythematosus. This study provides new insight into how such mutations can selectively damage the kidneys and may serve as a foundation for developing targeted therapies that block the activation of mutated RIG-I or its interaction with Y-RNA.

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