Study of human RIG-I polymorphisms identifies two variants with an opposite impact on the antiviral immune response

Abstract

Background: RIG-I is a pivotal receptor that detects numerous RNA and DNA viruses. Thus, its defectiveness may strongly impair the host antiviral immunity. Remarkably, very little information is available on RIG-I single-nucleotide polymorphisms (SNPs) presenting a functional impact on the host response. Methodology/Principal Findings: Here, we studied all non-synonymous SNPs of RIG-I using biochemical and structural modeling approaches. We identified two important variants: (i) a frameshift mutation (P229fs) that generates a truncated, constitutively active receptor and (ii) a serine to isoleucine mutation (S183I), which drastically inhibits antiviral signaling and exerts a down-regulatory effect, due to unintended stable complexes of RIG-I with itself and with MAVS, a key downstream adapter protein. Conclusions/Significance: Hence, this study characterized P229fs and S183I SNPs as major functional RIG-I variants and potential genetic determinants of viral susceptibility. This work also demonstrated that serine 183 is a residue that critically regulates RIG-I-induced antiviral signaling. © 2009 Pothlichet et al.