In this report, we identified a human MPYS SNP haplotype (HAQ) that encodes a R71H-G230A-R293Q amino acid sequence variant defective in stimulation of IFNβ production. In addition, we show that the IFNβ-stimulating defect of HAQ is caused by the R71H and R293Q.
The identification and study of this IFNβ-stimulating deficient SNPs haplotype (HAQ
) has led to important insight to the mechanism of MPYS function. Previous studies suggest that MPYS function as an adaptor protein that recruits IRF3 upon viral infection8
. However, we found that the loss-of-function HAQ mutant has similar IRF3 association as WT-MPYS (Supplementary Fig. 1a
). Furthermore, though the R293Q SNP is adjacent to a MPYS Traf2 binding site, it also has similar Traf2 binding as WT-MPYS (Supplementary 1b
). Thus the IFNβ defect in those SNPs is not easily explained by the adaptor model of MPYS. Instead, we found that SNP-adjacent cysteines, Cys-292 and C88
, are critical for IFNβ stimulation. We speculate that these SNPs may influence the function of adjacent critical cysteines, thus affect IFNβ stimulation.
In our cohorts, the HAQ/HAQ homozygosity accounts for ~3% of the total population (33 out of 1074). Interestingly, according to the frequency data in the dbSNPs, the H71-Q293 homozygosity frequency is almost 9 times higher in Asian (Han Chinese and Japanese) (~15%) than in European (~1.7%). Meanwhile, the H232/H232 homozygosity in Asian is about 1~2%, which is similar to what we found in American in this study (). This suggests that the HAQ haplotype, but not the H232, may be under natural selection.
MPYS is important for host defense against RNA and DNA viruses in mice 6, 7
, thus the HAQ
homozygous individuals may be susceptible to viral infection. Conversely, MPYS is also required for Listeria monocytogenes
-induced IFNβ response in fibroblasts and macrophages6
. Since Type I IFN mediates the susceptibility to Listeria monocytogenes
, these HAQ
individuals may be resistant to Listeria monocytogenes
infection. Furthermore, since MPYS mediates the adjuvant activity of DNA vaccines7
, these HAQ
individuals may be poor recipients for DNA vaccinations.
In conclusion, we have identified a novel MPYS SNP haplotype (HAQ) that is defective in transmission of signals leading to IFNβ production. Future studies should be directed at understanding the role of HAQ in various human infectious diseases.