The transcription factor forkhead box P3 (FOXP3) is essential for the development of regulatory T cells (Tregs) and their function in immune homeostasis. Previous studies have shown that in natural Tregs (nTregs), FOXP3 can be regulated by polyubiquitination and deubiquitination. However, the molecular players active in this pathway, especially those modulating FOXP3 by deubiquitination in the distinct induced Treg (iTreg) lineage, remain unclear. Here, we identify the ubiquitin‐specific peptidase 44 (USP44) as a novel deubiquitinase for FOXP3. USP44 interacts with and stabilizes FOXP3 by removing K48‐linked ubiquitin modifications. Notably, TGF‐β induces USP44 expression during iTreg differentiation. USP44 co‐operates with USP7 to stabilize and deubiquitinate FOXP3. Tregs genetically lacking USP44 are less effective than their wild‐type counterparts, both in vitro and in multiple in vivo models of inflammatory disease and cancer. These findings suggest that USP44 plays an important role in the post‐translational regulation of Treg function and is thus a potential therapeutic target for tolerance‐breaking anti‐cancer immunotherapy.

中文翻译：

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去泛素酶 USP44 通过阻止 FOXP3 降解来促进炎症期间的 Treg 功能。


转录因子叉头盒 P3 (FOXP3) 对于调节性 T 细胞 (Treg) 的发育及其在免疫稳态中的功能至关重要。先前的研究表明，在天然Tregs（nTregs）中，FOXP3可以通过多泛素化和去泛素化来调节。然而，在此通路中活跃的分子参与者，特别是那些在不同的诱导性 Treg (iTreg) 谱系中通过去泛素化来调节 FOXP3 的分子参与者仍不清楚。在这里，我们将泛素特异性肽酶 44 (USP44) 鉴定为 FOXP3 的新型去泛素酶。 USP44 通过去除 K48 连接的泛素修饰与 FOXP3 相互作用并稳定 FOXP3。值得注意的是，TGF-β 在 iTreg 分化过程中诱导 USP44 表达。 USP44 与 USP7 合作稳定 FOXP3 并使 FOXP3 去泛素化。无论是在体外还是在炎症性疾病和癌症的多种体内模型中，遗传上缺乏 USP44 的 Tregs 都比野生型 Treg 更有效。这些发现表明，USP44 在 Treg 功能的翻译后调节中发挥着重要作用，因此是打破耐受的抗癌免疫疗法的潜在治疗靶点。