Mutant RIG-I receptor induces renal inflammation through activation of Y-RNA

Researchers at the University Hospital Bonn (UKB) and the University of Bonn discovered how a small, naturally occurring RNA molecule in the kidney activates a mutated immune receptor, triggering a chain reaction. In collaboration with Singapore’s Nanyang Technological University and Würzburg University Hospital, among others, the study provides an explanation for how a point mutation in the immune receptor RIG-I turns the body’s defense system into a self-destructive force and causes severe autoimmune diseases of specific organs. The results have now been published in the journal Science Immunology.

RIG-I is an important sensor in the innate immune system that recognizes viral RNA and activates antiviral defenses. However, certain changes in the genetic material, known as mutations, can make RIG-I hypersensitive, causing the immune receptor to mistake the body’s RNA for viral invaders. The research team found that mice carrying a patient-associated RIG-I E373A mutation spontaneously developed lupus-like nephritis, a severe and often fatal inflammation of the kidneys. Unlike classical lupus, in which inflammation occurs due to immune complex deposits, the disease in these mice was caused by direct kidney inflammation triggered by mutant RIG-I.

Latent, tissue-specific activator of autoimmune inflammation

Further research showed that a short, non-coding RNA known as Y-RNA, which is produced in large amounts in the kidney, binds directly to the mutant RIG-I and triggers its abnormal activation.

We discovered that Y-RNA acts as a false alarm for the mutant RIG-I receptor, specifically in kidney cells. This local dysfunction of the immune system triggers severe inflammation similar to human lupus nephritis.”

Prof. Hiroki Kato, corresponding author, Director of the Institute of Cardiovascular Immunology at UKB and member of the ImmunoSensation Cluster of Excellence² at the University of Bonn

From molecular insights to disease mechanism

“Using advanced molecular and structural analyses, we were able to show that the RIG-I-E373A mutation binds to Y-RNA in an unusual way, leading to receptor activation even without viral infection,” says first author Saya Satoh, a PhD student at the University of Bonn in the research group of Prof. UKB. “This abnormal activation caused the kidney cells to produce large amounts of interferons and chemokines, which attracted immune system cells and caused inflammation.” However, the researchers were also able to identify a potential therapeutic target: blocking the so-called CCR2 signaling pathway, which recruits monocytes belonging to white blood cells, significantly reduced kidney inflammation in the affected mice.

Effect on autoimmune diseases

Mutations in RIG-I have been linked to rare inherited diseases such as Singleton-Merten syndrome (SMS) and systemic lupus erythematosus (SLE). This study provides important insights into how such mutations can selectively damage organs such as the kidney. These findings could pave the way for the development of targeted therapies that block the activation of mutant RIG-I or its interacting Y RNAs.

Participating agencies and funding:

In addition to UKB and the University of Bonn, the following institutions participated in the study: Nanyang Technological University, Singapore, Würzburg University Hospital, Germany, Okayama University, Japan, Kyoto University, Japan. The project was supported by the DFG, the German Excellence Strategy EXC 2151 “Nucleic Acid Immunity – Collaborative Research Center TRR237”, Open Philanthropy as part of the PANDEMIC ANTIVIRAL DISCOVERY PARTNERSHIP and the Singapore Ministry of Education MOE Award AcRF Tier1.