A common polymorphism in the caspase recruitment domain of RIG-I modifies the innate immune response of human dendritic cells.
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.
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Jianzhong
J
Hu
Estanislao
E
Nistal-Villán
Anu
A
Voho
Arnold
A
Ganee
Madhu
M
Kumar
Yaomei
Y
Ding
Adolfo
A
García-Sastre
James G
JG
Wetmur
D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000502:physiology; D020169:Caspases / Q000235:genetics; D002460:Cell Line; D002645:Chickens; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D009522:Newcastle disease virus / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011971:Receptors, Immunologic; D015533:Transcriptional Activation / Q000276:immunology
D053468:CARD Signaling Adaptor Proteins; D011971:Receptors, Immunologic; D016899:Interferon-beta; D020169:Caspases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases