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

Detecting viral RNA by the ubiquitously expressed cytosolic receptor retinoic acid-inducible gene I (RIG-I) is critical for antiviral immune responses, including type I interferon (IFN-I) and chemokine induction. RIG-I has evolved to sensitively recognize viral RNA but tolerate self-RNA. RIG-I mutations causing self-tolerance loss induce IFN-I and chemokines in patients, initiating autoinflammation. We observed that mice expressing the RIG-I patient variant E373A spontaneously developed lupus-like nephritis. Kidney-derived chemokines attracted monocytes through CCR2 (C-C motif chemokine receptor 2) and induced interstitial inflammation and tubular damage. This led to renal dysfunction independently of immunoglobulin G-nucleic acid complex deposition. Sequencing of RIG-I E373A-bound RNA from kidney-derived cells identified short noncoding Y-RNA. Deletion of the most enriched Y-RNA species reduced RIG-I E373A-induced IFN-I responses. Cryo-electron microscopy and molecular analyses revealed that RIG-I E373A binding to the Y-RNA stem region resulted in its activation. Thus, we demonstrate that Y-RNA activates a RIG-I gain-of-function mutant in a tissue-specific manner, causing autoinflammation culminating in lupus nephritis.