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TitleLocal activation of mutant RIG-I by short noncoding Y-RNA in the kidney triggers lethal nephritis.
Journal, issue, pagesSci Immunol, Vol. 10, Issue 112, Page eadx1135, Year 2025
Publish dateOct 31, 2025
AuthorsSaya Satoh / Yaw Bia Tan / Benjamin Heil / Shintaro Yamada / Verena Schütte / Celest Phang / Chaozhi Tang / Yuta Tsukamoto / Takahiro Higuchi / Takashi Fujita / Rayk Behrendt / Martin Schlee / Dahai Luo / Hiroki Kato /
PubMed AbstractDetecting 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 ...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.
External linksSci Immunol / PubMed:41171879
MethodsEM (single particle)
Resolution2.4 - 2.6 Å
Structure data

62568

9ktw

EMDB-62568, PDB-9ktw:
Cryo-EM structure of wild type RIG-I with 5'p-RNA
Method: EM (single particle) / Resolution: 2.6 Å

62574

9ku4

EMDB-62574, PDB-9ku4:
Cryo-EM structure of E373A mutant RIG-I with 5'p-RNA
Method: EM (single particle) / Resolution: 2.4 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsIMMUNE SYSTEM / RNA recognition / ATP hydrolysis / RLR signaling / RNA helicase

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