Dissecting the activation mechanisms of RIG-I pathogenic variant E373A and potential renal impact

Abstract

Gain-of-function (GOF) mutations in DDX58, which encodes RIG-I, can cause monogenic autoimmune diseases such as Singleton–Merten syndrome and systemic lupus erythematosus. In this study, we aim to elucidate the mechanisms of disease onset, focusing on self-RNA sensing of the RIG-I disease variant E373A. We found that mice harboring hRIG-I E373A (hRIG-I Tg) spontaneously developed lupus-like nephritis with interstitial inflammation, emulating clinical features observed in patients with a RIG-I GOF mutation. Chemokine production from the kidney in hRIG-I Tg was critical for triggering monocyte and T cell recruitment to cause kidney failure. Among RNAs bound to RIG-I E373A in a kidney cell line, we identified an RNA fraction that can activate RIG-I E373A as well as other RIG-I GOF mutants. Subsequent RNA-seq analysis revealed a non-coding RNA named RNY4, a member of the Y-RNA family, as the endogenous ligand of RIG-I E373A. Depletion of RNY4 in RIG-I E373A-expressing cells resulted in a significant reduction in IFN induction. RNA features of RNY4, such as 5'-terminal monophosphate and 3'- overhangs, prevented activation of RIG-I WT, whereas RIG-I E373A mutant overcame this inhibition and induced IFN in response to the RNY4. Notably, there was a positive correlation between Y-RNA expression levels and IFN-I responses in kidney cells. Taken together, these data highlight a potential role for Y RNA sensing of RIG-I GOF mutants in the development of kidney disease.