Local activation of mutant RIG-I by short noncoding Y-RNA in the kidney triggers lethal nephritis

Area of Science:

• Immunology
• Molecular Biology
• Pathology

Background:

• Retinoic acid-inducible gene I (RIG-I) is a cytosolic receptor crucial for detecting viral RNA and initiating antiviral immune responses, including type I interferon (IFN-I) production.
• Mutations in RIG-I that impair self-RNA tolerance can lead to autoinflammatory conditions due to inappropriate IFN-I and chemokine induction.
• Loss of self-tolerance in RIG-I can cause autoinflammation, presenting as various autoimmune diseases.

Purpose of the Study:

• To investigate the pathogenic mechanism of a specific RIG-I gain-of-function mutant (E373A) associated with autoinflammation.
• To determine the molecular basis of RIG-I E373A activation and its role in lupus-like nephritis.
• To identify the endogenous RNA species that activate the RIG-I E373A mutant in a tissue-specific manner.

Main Methods:

• Generation of mice expressing the RIG-I E373A patient variant.
• Analysis of kidney pathology, immune cell infiltration (monocytes via CCR2), and renal function.
• Sequencing of RIG-I E373A-bound RNA from kidney cells.
• Functional studies involving Y-RNA deletion to assess IFN-I responses.
• Cryo-electron microscopy and molecular analyses to elucidate RIG-I E373A-RNA interaction.

Main Results:

• Mice expressing RIG-I E373A spontaneously developed lupus-like nephritis characterized by interstitial inflammation and tubular damage.
• Kidney-derived chemokines attracted monocytes via CCR2, leading to renal dysfunction independent of immune complex deposition.
• Short noncoding Y-RNA was identified as the primary endogenous ligand activating RIG-I E373A in the kidneys.
• Deletion of specific Y-RNA species attenuated RIG-I E373A-mediated IFN-I responses.
• Cryo-electron microscopy revealed RIG-I E373A activation upon binding to the Y-RNA stem region.

Conclusions:

• Y-RNA can activate a RIG-I gain-of-function mutant in a tissue-specific manner, driving autoinflammation.
• This Y-RNA-mediated RIG-I activation is a key mechanism underlying lupus-like nephritis in the E373A mouse model.
• The findings elucidate a novel pathway linking self-RNA recognition defects in RIG-I to the pathogenesis of systemic autoimmune diseases.