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 1

USP47 positively correlates with intratumoral Treg signature.

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USP47 positively correlates with intratumoral Treg signature. (A) Gene s...
(A) Gene set enrichment analysis (GSEA) of Treg signature genes in USP47-expressing and USP47-silenced Tregs from The Cancer Genome Atlas (TCGA)–colon adenocarcinoma (COAD) database. NES, normalization enrichment score. (B) GSEA of Treg signature genes in USP47-expressing and USP47-silenced Tregs from 4 GEO data sets for COAD. (C) qRT-PCR analysis of Treg signature genes in tumor-infiltrating Tregs from CRC. The normalized USP47 expression value of tumor-infiltrating Tregs with the lowest expression of USP47 was set to be 1. The normalized USP47 expression values of USP47hi Tregs were more than 3 (n = 6), and those of USP47lo Tregs were less than 3 (n = 4). (D and E) qRT-PCR analysis of USP47 mRNA levels (D; n = 3) and immunoblot analysis of USP47 expression (E) in Tregs from PBMCs and CRC tissues. (F) qRT-PCR analysis of Treg signature genes in tumor-infiltrating Tregs from GC. The normalized USP47 expression value of tumor-infiltrating Tregs with the lowest expression of USP47 was set to be 1. The normalized USP47 expression values of USP47hi Tregs were more than 3 (n = 4), and those of USP47lo Tregs were less than 3 (n = 4). (G) qRT-PCR analysis of USP47 mRNA levels in Tregs from PBMCs and GC tissues (n = 3). Representative data are shown from 3 independent experiments (C–G). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01. Two-tailed Student’s t test (C, D, F, and G).