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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\u2013nucleic acid complex deposition. Sequencing of RIG-I E373A\u2013bound RNA from kidney-derived cells identified short noncoding Y-RNA. Deletion of the most enriched Y-RNA species reduced RIG-I E373A\u2013induced IFN-I responses. Cryo\u2013electron microscopy and molecular analyses revealed that RIG-I E373A binding to the Y-RNA stem region resulted in its activation. 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