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

MPYS/STING senses cyclic dinucleotides (CDNs) and generates type I IFNs. Here, we found that during out-of-Africa human migration, MPYS allele R71H-G230A-R293Q (HAQ) replaced G230A-R293Q (AQ). Using HAQ and AQ knock-in mice, we found that CDNs-type I IFNs responses were defective in HAQ but retained, in AQ mice suggesting that the CDNs-type I IFNs function of MPYS may be dispensable during human evolution. Adult AQ mice had less fat mass than HAQ or WT mice on a chow diet. AQ epididymal adipose tissue had increased Tregs and M2-macrophage with protein expression associated with enhanced fatty acid oxidation. Conditional knockout mice and adoptive cell transfer indicate a macrophage and Treg cell-intrinsic role of MPYS in fatty acid metabolism. Mechanistically, AQ/IFNAR1−/− mice had a similar lean phenotype as the AQ mice. MPYS intrinsic tryptophan fluorescence revealed that the R71H change increased MPYS hydrophilicity. Last, we found that the 2nd transmembrane (TM) and the TM2-TM3 linker region of MPYS interact with activated fatty acid, fatty acyl-CoA. Thus, MPYS modulates fatty acid metabolism, a function that may be critical during human evolution supporting the thrifty gene hypothesis.

MPYS/STING可感知环二核苷酸（CDNs）并产生I型干扰素。在此，我们发现在人类走出非洲的迁徙过程中，MPYS等位基因R71H - G230A - R293Q（HAQ）取代了G230A - R293Q（AQ）。利用HAQ和AQ基因敲入小鼠，我们发现CDNs - I型干扰素反应在HAQ小鼠中存在缺陷，但在AQ小鼠中得以保留，这表明MPYS的CDNs - I型干扰素功能在人类进化过程中可能是可有可无的。在普通饮食条件下，成年AQ小鼠的脂肪量比HAQ或野生型小鼠少。AQ附睾脂肪组织中调节性T细胞（Tregs）和M2型巨噬细胞增多，且与脂肪酸氧化增强相关的蛋白质表达增加。条件性基因敲除小鼠和过继性细胞转移实验表明，MPYS在脂肪酸代谢中具有巨噬细胞和Tregs细胞内在的作用。从机制上讲，AQ/IFNAR1−/−小鼠具有与AQ小鼠相似的消瘦表型。MPYS的固有色氨酸荧光显示，R71H的改变增加了MPYS的亲水性。最后，我们发现MPYS的第二个跨膜区（TM）以及TM2 - TM3连接区与活化的脂肪酸、脂肪酰基辅酶A相互作用。因此，MPYS可调节脂肪酸代谢，这一功能在人类进化过程中可能至关重要，支持了节俭基因假说。