MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs

Abstract

MPYS/STING (stimulator of IFN genes) senses cyclic dinucleotides (CDNs), generates type I IFNs, and plays a critical role in infection, inflammation, and cancer. In this study, analyzing genotype and haplotype data from the 1000 Genomes Project, we found that the R71H-G230A-R293Q (HAQ) MPYS allele frequency increased 57-fold in East Asians compared with sub-Saharan Africans. Meanwhile, the G230A-R293Q (AQ) allele frequency decreased by 98% in East Asians compared with sub-Saharan Africans. We propose that the HAQ and AQ alleles underwent a natural selection during the out-of-Africa migration. We used mouse models of HAQ and AQ to investigate the underlying mechanism. We found that the mice carrying the AQ allele, which disappeared in East Asians, had normal CDN–type I IFN responses. Adult AQ mice, however, had less fat mass than did HAQ or wild-type mice on a chow diet. AQ epididymal adipose tissue had increased regulatory T cells and M2 macrophages with protein expression associated with enhanced fatty acid oxidation. Conditional knockout mice and adoptive cell transfer indicate a macrophage and regulatory T cell–intrinsic role of MPYS in fatty acid metabolism. Mechanistically, AQ/IFNAR1−/− mice had a similar lean phenotype as for the AQ mice. MPYS intrinsic tryptophan fluorescence revealed that the R71H change increased MPYS hydrophilicity. Lastly, we found that the second transmembrane (TM) and the TM2–TM3 linker region of MPYS interact with activated fatty acid, fatty acyl–CoA. In summary, studying the evolution of the human MPYS gene revealed an MPYS function in modulating fatty acid metabolism that may be critical during the out-of-Africa migration.

The commonTMEM173 HAQ, AQalleles rescue CD4 T cellpenia, restore T-regs, and preventSAVI (N153S)inflammatory disease in mice

“…AQ mice are lean while HAQ mice are fat 34 . Most importantly, HAQ was positively selected, while AQ was negatively selected, in modern humans outside Africans 34 . Thus, the death pathway of STING is also distinct from the STING function that was naturally selected.…”

“…However, in East Asians, WT/HAQ (34.3%), not WT/WT (22.0%), is the most common TMEM173 genotype 32 . Critically, the HAQ allele was positively selected in modern humans outside Africa 33 . Anatomically modern humans outside Africa are descendants of a single Out-of-Africa Migration 50,000∼70,000 years ago.…”

“…Importantly, the AQ allele was negatively selected outside Africa 33 . ∼40.1% of Africans are AQ carriers, while ∼0.4% of East Asians have the AQ allele 33 . Importantly, TMEM173 alleles often have a dominant negative effect because the protein product STING exists as a homodimer 25,34 .…”

“…Anatomically modern humans outside Africa are descendants of a single Out-of-Africa Migration 50,000∼70,000 years ago. ∼1.4% of Africans have the HAQ allele, while ∼63.9% of East Asians are HAQ carriers 34 . Haplotype analysis revealed that HAQ was derived from G230A-R293Q ( AQ ) allele 34 .…”

“…∼1.4% of Africans have the HAQ allele, while ∼63.9% of East Asians are HAQ carriers 34 . Haplotype analysis revealed that HAQ was derived from G230A-R293Q ( AQ ) allele 34 . Importantly, the AQ allele was negatively selected outside Africa 34 .…”