ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation.
ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation.
复制标题
CUL3-KLHL25 的 ACLY 泛素化诱导脂肪酸代谢重编程，促进 iTreg 分化
作者：
Tian M;Hao F;Jin X;Sun X;Jiang Y;Wang Y;Li D;Chang T;Zou Y;Peng P;Xia C;Liu J;Li Y;Wang P;Feng Y;Wei M
可诱导调节性T细胞(ITreg)在免疫抑制中发挥核心作用。随着iTreg细胞从激活的T(Th0)细胞分化出来，细胞代谢发生了戏剧性的变化，包括从脂肪酸合成(Fas)转变为脂肪酸氧化(FAO)。尽管脂肪酸代谢中的重编程是至关重要的，但在iTreg分化过程中调节这一过程的机制仍然不清楚。在此，我们发现在转化生长因子β-1(转化生长因子-β-1)刺激下，iTreg分化过程中，三磷酸腺苷-柠檬酸裂解酶的活性明显下降。这种减少是由于CUL3-KLHL25介导的ACLY泛素化和降解所致。结果，Fas中能够抑制粮农组织限速酶肉碱棕榈酰转移酶1(CPT1)的代谢中间体丙二酰辅酶A(Malonyl-CoA)减少。因此，ACLY泛素化和降解促进了粮农组织，从而促进了iTreg的分化。综上所述，我们建议转化生长因子β1-CUL3-KLHL25-ACLY轴作为调节iTreg分化的重要手段，为维持免疫动态平衡预防免疫性疾病带来启示。
Inducible regulatory T (iTreg) cells play a central role in immune suppression. As iTreg cells are differentiated from activated T (Th0) cells, cell metabolism undergoes dramatic changes, including a shift from fatty acid synthesis (FAS) to fatty acid oxidation (FAO). Although the reprogramming in fatty acid metabolism is critical, the mechanism regulating this process during iTreg differentiation is still unclear. Here we have revealed that the enzymatic activity of ATP-citrate lyase (ACLY) declined significantly during iTreg differentiation upon transforming growth factor β1 (TGFβ1) stimulation. This reduction was due to CUL3-KLHL25-mediated ACLY ubiquitination and degradation. As a consequence, malonyl-CoA, a metabolic intermediate in FAS that is capable of inhibiting the rate-limiting enzyme in FAO, carnitine palmitoyltransferase 1 (CPT1), was decreased. Therefore, ACLY ubiquitination and degradation facilitate FAO and thereby iTreg differentiation. Together, we suggest TGFβ1-CUL3-KLHL25-ACLY axis as an important means regulating iTreg differentiation and bring insights into the maintenance of immune homeostasis for the prevention of immune diseases.