A common polymorphism in the caspase recruitment domain of RIG-I modifies the innate immune response of human dendritic cells

J Immunol. 2010 Jul 1;185(1):424-32. doi: 10.4049/jimmunol.0903291. Epub 2010 May 28.

Abstract

Infection of human dendritic cells (DCs) by negative-strand RNA viruses, such as Newcastle disease virus, leads to the induction of the IFNbeta gene, IFNB1, through the activation of the RNA helicase RIG-I, which is encoded by DDX58. Expression levels of IFNB1 and DDX58 in infected DCs showed positive correlations at the population and the single-cell levels. DDX58 has a common and potentially functional single nucleotide polymorphism, rs10813831 (A/G), encoding an Arg7Cys amino acid change in the RIG-I protein caspase recruitment domain (CARD). Quantitative RT-PCR analysis on Newcastle disease virus-infected primary DCs from 130 individuals revealed a significant association of the Arg7Cys single nucleotide polymorphism with increased IFNB1 and DDX58 transcription. Allelic imbalance analysis ruled out allele-specific DDX58 message levels and suggested that the observed association between Arg7Cys and IFNB1 and DDX58 transcription originated from a functional change in RIG-I due to the amino acid substitution in the CARD. DDX58 transfection experiments in 293T cells confirmed a biological functional difference between RIG-I 7Cys and the more common RIG-I 7Arg. Taken together, these data indicate that the innate immune response to viral infection of human cells is modified by a functional polymorphism in the RIG-I CARD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / genetics*
  • CARD Signaling Adaptor Proteins / physiology
  • Caspases / genetics
  • Cell Line
  • Chickens
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / biosynthesis
  • DEAD-box RNA Helicases / genetics*
  • DEAD-box RNA Helicases / metabolism
  • DEAD-box RNA Helicases / physiology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Dendritic Cells / virology
  • Humans
  • Immunity, Innate / genetics*
  • Interferon-beta / biosynthesis
  • Interferon-beta / genetics
  • Newcastle disease virus / immunology
  • Polymorphism, Single Nucleotide / immunology*
  • Protein Structure, Tertiary / genetics
  • Receptors, Immunologic
  • Transcriptional Activation / immunology

Substances

  • CARD Signaling Adaptor Proteins
  • Receptors, Immunologic
  • Interferon-beta
  • Caspases
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases