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The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation
Author(s) -
Yang Jing,
Wei Ping,
Barbi Joseph,
Huang Qianru,
Yang Evan,
Bai Yakun,
Nie Jia,
Gao Yanhang,
Tao Jinhui,
Lu Ying,
Xie Chichu,
Hou Xiaoxia,
Ren Jiazi,
Wu Xingmei,
Meng Jian,
Zhang Ying,
Fu Juan,
Kou Wei,
Gao Yayi,
Chen Zuojia,
Liang Rui,
Tsun Andy,
Li Dan,
Guo Wenzhi,
Zhang Shuijun,
Zheng SongGuo,
Niu Junqi,
Galardy Paul,
Tong Xuemei,
Shi Guochao,
Li Huabin,
Pan Fan,
Li Bin
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050308
Subject(s) - deubiquitinating enzyme , foxp3 , ubiquitin , microbiology and biotechnology , inflammation , biology , transcription factor , forkhead transcription factors , regulatory t cell , immune system , cancer research , immunology , gene , t cell , genetics , il 2 receptor
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.