The functional integrity of Tregs is interwoven with cellular metabolism; however, the mechanisms governing Treg metabolic programs remain elusive. Here, we identified that the deubiquitinase USP47 inhibited c-Myc translation mediated by the RNA N⁶-methyladenosine (m⁶A) reader YTHDF1 to maintain Treg metabolic and functional homeostasis. USP47 positively correlated with the tumor-infiltrating Treg signature in samples from patients with colorectal cancer and gastric cancer. USP47 ablation compromised Treg homeostasis and function in vivo, resulting in the development of inflammatory disorders, and boosted antitumor immune responses. USP47 deficiency in Tregs triggered the accumulation of the c-Myc protein and in turn exacerbated hyperglycolysis. Mechanistically, USP47 prevented YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m⁶A-based c-Myc translation efficiency. Our findings reveal that USP47 directs m⁶A-dependent metabolic programs to orchestrate Treg homeostasis and suggest novel approaches for selective immune modulation in cancer and autoimmune diseases by targeting of USP47.

中文翻译：

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USP47 抑制 m6A 依赖性 c-Myc 翻译以维持调节性 T 细胞代谢和功能稳态

Tregs 的功能完整性与细胞代谢交织在一起；然而，控制 Treg 代谢程序的机制仍然难以捉摸。在这里，我们发现去泛素酶 USP47 抑制 RNA N ⁶ -甲基腺苷 (m ⁶ A) 阅读器 YTHDF1 介导的 c-Myc 翻译，以维持 Treg 代谢和功能稳态。USP47 与结直肠癌和胃癌患者样本中的肿瘤浸润 Treg 特征呈正相关。USP47 消融会损害体内 Treg 稳态和功能，导致炎症性疾病的发展，并增强抗肿瘤免疫反应。Tregs 中的 USP47 缺陷引发了 c-Myc 蛋白的积累，进而加剧了糖酵解过度。从机制上讲，USP47 阻止 YTHDF1 泛素化，从而减弱 YTHDF1 与翻译起始机制的关联，从而降低基于 m ⁶ A 的 c-Myc 翻译效率。我们的研究结果表明，USP47 指导 m ⁶ A 依赖性代谢程序来协调 Treg 稳态，并提出了通过靶向 USP47 来选择性调节癌症和自身免疫性疾病的新方法。