MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs.
MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs.
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DOI：
10.4049/jimmunol.2200158
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发表时间：
2022-12-01
期刊：
影响因子：
--
通讯作者：
Jin L
中科院分区：
文献类型：
--
作者：
Mansouri S;Gogoi H;Patel S;Katikaneni DS;Singh A;Aybar-Torres A;de Lartigue G;Jin L
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。
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.
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DOI：
10.1007/978-1-4939-6820-6_6
发表时间：
2017-01-01
期刊：
THERMOGENIC FAT
影响因子：
--
作者：
Brestoff, Jonathan R.
通讯作者：
Brestoff, Jonathan R.
影响因子：
64.5
作者：
Buck MD;Sowell RT;Kaech SM;Pearce EL
通讯作者：
Pearce EL
影响因子：
17.1
作者：
Bader, Cameron S.;Barreras, Henry;Levy, Robert B.
通讯作者：
Levy, Robert B.
影响因子：
64.8
作者：
Donnelly CR;Jiang C;Andriessen AS;Wang K;Wang Z;Ding H;Zhao J;Luo X;Lee MS;Lei YL;Maixner W;Ko MC;Ji RR
通讯作者：
Ji RR
影响因子：
64.8
作者：
Choudhury A;Aron S;Botigué LR;Sengupta D;Botha G;Bensellak T;Wells G;Kumuthini J;Shriner D;Fakim YJ;Ghoorah AW;Dareng E;Odia T;Falola O;Adebiyi E;Hazelhurst S;Mazandu G;Nyangiri OA;Mbiyavanga M;Benkahla A;Kassim SK;Mulder N;Adebamowo SN;Chimusa ER;Muzny D;Metcalf G;Gibbs RA;TrypanoGEN Research Group;Rotimi C;Ramsay M;H3Africa Consortium;Adeyemo AA;Lombard Z;Hanchard NA
通讯作者：
Hanchard NA