A novel RNF125 variant associated with Tenorio syndrome alters ubiquitin chain binding

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Retinoic acid-inducible gene I (RIG-I) signaling is crucial for viral clearance.
• RIG-I activation by viral dsRNA involves lysine 63-linked ubiquitin chains.
• Termination of RIG-I signaling requires lysine 48-linked ubiquitin chains.

Purpose of the Study:

• To identify and characterize a novel RNF125 gene variant associated with Tenorio syndrome.
• To investigate the functional impact of this variant on RNF125's role in ubiquitin chain modification and RIG-I signaling.

Main Methods:

• Genetic sequencing to identify the RNF125 variant.
• In vitro assays to assess E3 ligase activity and ubiquitin chain interaction.
• Analysis of clinical phenotypes in the affected individual.

Main Results:

• A novel RNF125 variant (c.670G>C p.Glu224Gln) was identified in an individual with Tenorio syndrome.
• The variant is located in the ubiquitin interaction motif (UIM) of RNF125.
• While E3 ligase activity is retained, the variant shows impaired interaction with lysine 63-linked ubiquitin chains.

Conclusions:

• The UIM of RNF125 likely binds lysine 63-linked ubiquitin chains.
• This interaction is essential for the normal function of RNF125 in terminating RIG-I signaling.
• The identified variant provides new insights into the molecular mechanisms of Tenorio syndrome and immune regulation.