USP22 controls iNKT immunity through MED1 suppression of histone H2A monoubiquitination

Yana Zhang, Yajun Wang, Beixue Gao, Yueqi Sun, Liang Cao, Samantha M. Genardi, Chyung Ru Wang, Hua Bin Li, Zhaolin Sun*, Yanjie Yang, Deyu Fang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article numbere20182218
JournalJournal of Experimental Medicine
Issue number5
StatePublished - May 4 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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