Identification and characterization of a loss-of-function human MPYS variant.
MPYS, also known as STING and MITA, is an interferon (IFN)β stimulator essential for host defense against RNA, DNA viruses and intracellular bacteria. MPYS also facilitates the adjuvant activity of DNA vaccines. Here, we report identification of a distinct human MPYS haplotype that contains three non-synonymous single nucleotide polymorphisms (SNPs), R71H-G230A-R293Q (thus, named the HAQ haplotype). We estimate, in two cohorts (1,074 individuals), that ∼3% of Americans are homozygous for this HAQ haplotype. HAQ MPYS exhibits a > 90% loss in the ability to stimulate IFNβ production. Furthermore, fibroblasts and macrophage cells expressing HAQ are defective in Listeria monocytogenes infection-induced IFNβ production. Lastly, we find that the loss of IFNβ activity is due primarily to the R71H and R293Q SNPs in HAQ. We hypothesize that individuals carrying HAQ may exhibit heightened susceptibility to viral infection and respond poorly to DNA vaccines.
Integrated Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, CO 80206-2762, USA.
L
L
Jin
L-G
LG
Xu
I V
IV
Yang
E J
EJ
Davidson
D A
DA
Schwartz
M M
MM
Wurfel
J C
JC
Cambier
D000595:Amino Acid Sequence; D000818:Animals; D015331:Cohort Studies; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D008969:Molecular Sequence Data; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D000099197:STING Protein
D016899:Interferon-beta; D008565:Membrane Proteins; C532857:STING1 protein, human; D000099197:STING Protein
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