The ubiquitin pathway has been shown to regulate iNKT cell immunity, but the deubiquitinase involved in this process has not been identified. Herein we found that ubiquitin-specific peptidase 22 (USP22) is highly expressed in iNKT cells during their early developmental stage 1. USP22 deficiency blocked the transition from stage 1 to 2 during iNKT cell development in a cell-intrinsic manner. USP22 suppression also diminishes iNKT17 and iNKT1 differentiation but favors iNKT2 polarization without altering conventional T cell activation and differentiation. USP22 interacts with the Mediator complex subunit 1 (MED1), a transcription coactivator involved in iNKT cell development. Interestingly, while interacting with MED1, USP22 does not function as a deubiquitinase to suppress MED1 ubiquitination for its stabilization. Instead, USP22 enhances MED1 functions for IL-2Rβ and T-bet gene expression through deubiquitinating histone H2A but not H2B monoubiquitination. Therefore, our study revealed USP22-mediated histone H2A deubiquitination fine-tunes MED1 transcriptional activation as a previously unappreciated molecular mechanism to control iNKT development and functions.

中文翻译：

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USP22 通过 MED1 抑制组蛋白 H2A 单泛素化来控制 iNKT 免疫

泛素途径已被证明可以调节 iNKT 细胞免疫，但参与该过程的去泛素酶尚未确定。在此，我们发现泛素特异性肽酶 22 (USP22) 在 iNKT 细胞早期发育第 1 阶段中高表达。USP22 缺陷以细胞固有的方式阻止了 iNKT 细胞发育过程中从第 1 阶段到第 2 阶段的转变。USP22 抑制还会减少 iNKT17 和 iNKT1 分化，但有利于 iNKT2 极化，而不改变传统 T 细胞激活和分化。USP22 与介导复合体亚基 1 (MED1) 相互作用，MED1 是一种参与 iNKT 细胞发育的转录共激活因子。有趣的是，在与 MED1 相互作用时，USP22 并不充当去泛素酶来抑制 MED1 泛素化以使其稳定。相反，USP22 通过组蛋白 H2A 去泛素化而非 H2B 单泛素化来增强 MED1 对 IL-2Rβ 和 T-bet 基因表达的功能。因此，我们的研究揭示了 USP22 介导的组蛋白 H2A 去泛素化微调 MED1 转录激活，作为一种以前未被认识到的控制 iNKT 发育和功能的分子机制。