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J Exp Med. 2020 May 4;217(5). doi: 10.1084/jem.20182218.

USP22 controls iNKT immunity through MED1 suppression of histone H2A monoubiquitination.

Author information

1
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL.
2
Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL.
3
Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China.
4
Department of Pharmacology, Dalian Medical University, Dalian, China.
5
Psychology Department of the Public Health Institute of Harbin Medical University, Harbin, China.

Abstract

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.

PMID:
32069354
DOI:
10.1084/jem.20182218

Conflict of interest statement

Disclosures: The authors declare no competing interests exist.

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