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.
USP22 controls iNKT immunity through MED1 suppression of histone H2A monoubiquitination
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Yana Zhang, Yajun Wang, Beixue Gao, Yueqi Sun, Liang Cao, Samantha M. Genardi, Chyung-Ru Wang, HuaBin Li, Zhaolin Sun, Yanjie Yang, Deyu Fang; USP22 controls iNKT immunity through MED1 suppression of histone H2A monoubiquitination. J Exp Med 4 May 2020; 217 (5): e20182218. doi: https://doi.org/10.1084/jem.20182218
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