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.

中文翻译：

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CUL3-KLHL25 的 ACLY 泛素化诱导脂肪酸代谢重编程以促进 iTreg 分化

诱导型调节性 T (iTreg) 细胞在免疫抑制中发挥核心作用。随着 iTreg 细胞从活化的 T (Th0) 细胞分化而来，细胞代谢发生了巨大的变化，包括从脂肪酸合成 (FAS) 到脂肪酸氧化 (FAO) 的转变。尽管脂肪酸代谢中的重编程至关重要，但在 iTreg 分化过程中调节这一过程的机制仍不清楚。在这里，我们发现 ATP-柠檬酸裂解酶 (ACLY) 的酶活性在转化生长因子 β1 (TGFβ1) 刺激后的 iTreg 分化过程中显着下降。这种减少是由于 CUL3-KLHL25 介导的 ACLY 泛素化和降解。因此，丙二酰辅酶A（FAS中的一种代谢中间体，能够抑制FAS中的限速酶肉碱棕榈酰转移酶1（CPT1），减少了。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。总之，我们建议将 TGFβ1-CUL3-KLHL25-ACLY 轴作为调节 iTreg 分化的重要手段，并为维持免疫稳态以预防免疫疾病带来见解。