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


RESULTS
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 (P(229)fs) that generates a truncated, constitutively active receptor and (ii) a serine to isoleucine mutation (S(183)I), 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
Hence, this study characterized P(229)fs and S(183)I 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.
Pothlichet
Julien
J
Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France.
Burtey
Anne
A
Kubarenko
Andriy V
AV
Caignard
Gregory
G
Solhonne
Brigitte
B
Tangy
Frédéric
F
Ben-Ali
Meriem
M
Quintana-Murci
Lluis
L
Heinzmann
Andrea
A
Chiche
Jean-Daniel
JD
Vidalain
Pierre-Olivier
PO
Weber
Alexander N R
AN
Chignard
Michel
M
Si-Tahar
Mustapha
M
D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D019281:Dimerization; D014644:Genetic Variation; D006801:Humans; D007107:Immune System; D007113:Immunity, Innate; D008957:Models, Genetic; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic; D015398:Signal Transduction
D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases