USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis
Aiting Wang, Haiyan Huang, Jian-Hong Shi, Xiaoyan Yu, Rui Ding, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Xia Li, Ren Zhao, Qiang Zou
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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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 5

USP47 restricts c-Myc–dependent Treg hyperglycolysis.

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USP47 restricts c-Myc–dependent Treg hyperglycolysis. (A) Heatmap of c-M...
(A) Heatmap of c-Myc–associated genes in Tregs stimulated with anti-CD3 and anti-CD28 for 24 hours. (B) Immunoblot analysis of Tregs stimulated with anti-CD3 and anti-CD28 antibodies for 0, 3, or 6 hours. (C) c-Myc expression levels in Foxp3+YFP+ and Foxp3+YFP– Tregs in the spleen from 3-month-old Usp47fl/flFoxp3-Cre/+ female mice stimulated with anti-CD3 and anti-CD28 antibodies for 3 hours (n = 4). (D) qRT-PCR analysis of c-Myc mRNA levels in Tregs stimulated with anti-CD3 and anti-CD28 antibodies for 0, 3, or 6 hours (n = 3). (E) Extracellular acidification rates (ECAR) of Tregs stimulated with anti-CD3 and anti-CD28 antibodies for 3 hours under basal conditions (Bas) or at maximum (Max) with the addition of glucose (Glu), oligomycin (Oli), and 2-deoxy-d-glucose (2-DG) (n = 6). (F) Oxygen consumption rates (OCR) of Tregs stimulated with anti-CD3 and anti-CD28 antibodies for 3 hours under basal conditions (Bas) or at maximum (Max) with the addition of oligomycin, the mitochondrial uncoupler FCCP, and rotenone plus antimycin A (R+A) (n = 6). (G) ECAR of Tregs stimulated with anti-CD3 and anti-CD28 antibodies for 3 hours in the presence of 100 μM 10058-F4 (F4) (n = 8). Ctrl, DMSO. (H) CD45.1+ conventional CD4+ T cells (Tconv) were injected i.v. into Rag1-KO mice alone or with an equal number of CD45.2+ Usp47+/+Foxp3-Cre (WT) or Usp47fl/flFoxp3-Cre (KO) Tregs pretreated with anti-CD3 and anti-CD28 antibodies plus 2 mM 2-DG or 100 μM 10058-F4 (F4) for 6 hours. Day 7 after cell transfer, cells were isolated from spleen (n = 5). Data shown are representative of 3 (B–H) independent experiments and are presented as mean ± SEM. Two-tailed Student’s t test (C–F) or 1 -way ANOVA (G and H). *P < 0.05; **P < 0.01.