TMEM173 encodes MPYS/STING and is an innate immune sensor for cyclic dinucleotides (CDNs) playing a critical role in infection, inflammation, and cancer. The R71H-G230A-R293Q (HAQ) of TMEM173 is the second most common human TMEM173 allele. In this study, using data from the 1000 Genomes Project we found that homozygous HAQ individuals account for ∼16.1% of East Asians and ∼2.8% of Europeans whereas Africans have no homozygous HAQ individuals. Using B cells from homozygous HAQ carriers, we found, surprisingly, that HAQ/HAQ carriers express extremely low MPYS protein and have a decreased TMEM173 transcript. Consequently, the HAQ/HAQ B cells do not respond to CDNs. We subsequently generated an HAQ knock-in mouse expressing a mouse equivalent of the HAQ allele (mHAQ). The mHAQ mouse has decreased MPYS protein in B cells, T cells, Ly6Chi monocytes, bone marrow–derived dendritic cells, and lung tissue. The mHAQ mouse also does not respond to CDNs in vitro and in vivo. Lastly, Pneumovax 23, with an efficacy that depends on TMEM173, is less effective in mHAQ mice than in wild type mice. We conclude that HAQ is a null TMEM173 allele. Our findings have a significant impact on research related to MPYS-mediated human diseases and medicine.
This article is featured in In This Issue, p.555
This work was supported by National Institute of Allergy and Infectious Diseases Grants 1R56AI110606, 1R01AI110606, R21AI099346 Subcontract, and 1R21AI125999 (to L.J.), the Gary and Janis Grover Young Scientist Award (to L.J.), the Deutsche Forschungsgemeinschaft (DFG) Grant OP 86/10-1 and Sonderforschungsbereich Grant SFB-TR84 (both to B.O.), and DFG Grant GRK1673 (to J.S.R.-M. and B.O.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- bone marrow
- BM-derived dendritic cell
- BM-derived macrophage
- cyclic di-AMP
- cyclic di-GMP
- cyclic dinucleotide
- 2′5-3′5′-cyclic GMP-AMP
- Genotype-Tissue Expression
- heat-killed Streptococcus pneumoniae
- a knock-in mouse expressing the mouse equivalent of the human HAQ
- pneumococcal polysaccharide type 2
- pneumococcal polysaccharide type 3
- pneumococcal surface protein A
- quantitative PCR
- radioimmunoprecipitation assay
- single-nucleotide polymorphism
- wild type.
- Received September 9, 2016.
- Accepted November 6, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.