An autoinflammatory RIG-I variant causing Singleton-Merten syndrome associates with small non-coding Y-RNAs

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The RNA sensor retinoic acid-inducible gene I (RIG-I) is vital for detecting viral RNA and initiating antiviral responses.
• Gain-of-function variants in RIG-I cause Singleton-Merten syndrome (SMS) by aberrant self-RNA sensing, leading to excessive type I interferon production.
• The specific self-RNAs recognized by these pathogenic RIG-I variants remain largely unknown.

Purpose of the Study:

• To identify the self-RNAs that bind to a specific ATPase-deficient gain-of-function RIG-I variant (RIG-I^C268F).
• To understand the role of these bound self-RNAs in the sterile immune activation characteristic of SMS.

Main Methods:

• Utilized infrared individual-nucleotide resolution UV-crosslinking and immunoprecipitation (irCLIP) to profile RNA bound to RIG-I^C268F.
• Employed native RNA immunoprecipitation to confirm specific RNA-protein interactions.

Main Results:

• irCLIP identified a wide range of self-RNAs bound to RIG-I^C268F, predominantly transcribed by RNA polymerase III.
• Confirmed a significant interaction between RIG-I^C268F and Y-RNAs, a family of small non-coding RNAs.
• Targeting Y-RNAs alone did not fully abolish RIG-I-mediated interferon responses, suggesting involvement of other RNA polymerase III transcripts.

Conclusions:

• Gain-of-function RIG-I variants interact with a broad spectrum of self-RNAs, not limited to Y-RNAs.
• RNA polymerase III-transcribed RNAs are key players in the aberrant activation of RIG-I in SMS.
• Further elucidation of the complete RNA profile is necessary for a comprehensive understanding of SMS pathogenesis.