Human RIG-I Antiviral Deficiency Caused by a Dominant-Negative Variant Locked in a Signaling-Inactive State.

Area of Science:

• Immunology
• Virology
• Human Genetics

Background:

• RIG-I (Retinoic acid-inducible gene I) is a crucial cytosolic sensor for viral RNA, initiating innate immune responses.
• The physiological significance of RIG-I in human immunity is not fully understood due to a lack of reported deficiency cases.

Purpose of the Study:

• To investigate the role of RIG-I in human antiviral immunity.
• To characterize a novel RIG-I loss-of-function variant identified in a severe COVID-19 patient.

Main Methods:

• Genetic sequencing to identify mutations in a critically ill COVID-19 patient.
• In vitro functional assays to assess the impact of the RIG-I G731R variant on ATPase activity, RNA binding, and signaling.
• Analysis of dominant-negative effects and structure-function relationships.

Main Results:

• A novel heterozygous RIG-I G731R variant was identified in a severe COVID-19 patient, causing a dominant loss-of-function.
• The G731R mutation impairs RIG-I ATPase activity by disrupting the arginine finger, but not RNA binding.
• G731R inhibits wild-type RIG-I function, leading to impaired IFN-β response and highlighting the importance of uncompromised RIG-I.

Conclusions:

• Uncompromised RIG-I function is essential for effective human antiviral immunity.
• The RIG-I G731R variant demonstrates a dominant negative effect, impacting innate immune responses.
• Specific substitutions at G731 have pleiotropic effects, influencing RIG-I gain or loss of function.