9KTW

Cryo-EM structure of wild type RIG-I with 5'p-RNA

Summary for 9KTW

• Entry DOI: 10.2210/pdb9ktw/pdb
• EMDB information: 62568
• Descriptor: Antiviral innate immune response receptor RIG-I, 5'p-RNA (60-MER), ZINC ION (3 entities in total)
• Functional Keywords: rna recognition, atp hydrolysis, rlr signaling, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 126048.38

Authors

Tan, Y.B.,Luo, D. (deposition date: 2024-12-03, release date: 2025-12-03, Last modification date: 2026-06-17)

Primary citation

Satoh, S.,Tan, Y.B.,Heil, B.,Yamada, S.,Schutte, V.,Phang, C.,Tang, C.,Tsukamoto, Y.,Higuchi, T.,Fujita, T.,Behrendt, R.,Schlee, M.,Luo, D.,Kato, H.
Local activation of mutant RIG-I by short noncoding Y-RNA in the kidney triggers lethal nephritis.
Sci Immunol, 10:eadx1135-eadx1135, 2025

PubMed Abstract: 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.

PubMed: 41171879
DOI: 10.1126/sciimmunol.adx1135

Experimental method

ELECTRON MICROSCOPY (2.6 Å)