USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis
Aiting Wang, … , Ren Zhao, Qiang Zou
Aiting Wang, … , Ren Zhao, Qiang Zou
Published October 3, 2023
Citation Information: J Clin Invest. 2023;133(23):e169365. https://doi.org/10.1172/JCI169365.
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Research Article Autoimmunity Immunology

USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis

Abstract

The functional integrity of Tregs is interwoven with cellular metabolism; however, the mechanisms governing Treg metabolic programs remain elusive. Here, we identified that the deubiquitinase USP47 inhibited c-Myc translation mediated by the RNA N6-methyladenosine (m6A) reader YTHDF1 to maintain Treg metabolic and functional homeostasis. USP47 positively correlated with the tumor-infiltrating Treg signature in samples from patients with colorectal cancer and gastric cancer. USP47 ablation compromised Treg homeostasis and function in vivo, resulting in the development of inflammatory disorders, and boosted antitumor immune responses. USP47 deficiency in Tregs triggered the accumulation of the c-Myc protein and in turn exacerbated hyperglycolysis. Mechanistically, USP47 prevented YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m6A-based c-Myc translation efficiency. Our findings reveal that USP47 directs m6A-dependent metabolic programs to orchestrate Treg homeostasis and suggest novel approaches for selective immune modulation in cancer and autoimmune diseases by targeting of USP47.

Authors

Aiting Wang, Haiyan Huang, Jian-Hong Shi, Xiaoyan Yu, Rui Ding, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Xia Li, Ren Zhao, Qiang Zou

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Figure 3

USP47 ablation dampens Treg functions in vivo.

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USP47 ablation dampens Treg functions in vivo. (A–E) Three-month-old Usp...
(A–E) Three-month-old Usp47+/+Foxp3-Cre and Usp47fl/flFoxp3-Cre mice were provided with drinking water containing 2.5% DSS for 7 days, followed by regular water. Mice were killed at day 9. They were analyzed for colon length (A and B; n = 3), H&E staining of colon section (C; scale bars: 500 μm), and images of mini-endoscopic colon (D). Flow cytometric analysis of the proportions of IFN-γ– or IL-17–producing CD4+ and CD8+ T cells in the mLNs and lamina propria lymphocytes (LPL) from mice after DSS-induced colitis (E; n = 4 or 5). (F and G) Ten-week-old Usp47+/+Foxp3-Cre and Usp47fl/flFoxp3-Cre mice were injected subcutaneously with MC38 colon cancer cells, and 15 days after injection, mice were sacrificed. Tumor growth in 10-week-old Usp47+/+Foxp3-Cre and Usp47fl/flFoxp3-Cre mice injected with MC38 colon cancer cells (F; n = 5). Flow cytometric analysis of the percentages of IFN-γ–producing CD4+ and CD8+ T cells in the tumors from Usp47+/+Foxp3-Cre and Usp47fl/flFoxp3-Cre mice injected with MC38 tumor cells (G; n = 4). Representative data are shown from 3 independent experiments. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01. Two-tailed Student’s t test (B, E–G).