USP47 inhibits [m.sup.6]A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis

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 [N.sup.6]-methyladenosine ([m.sup.6]A) reader YTHDF1 t...

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Bibliographic Details
Published in:The Journal of clinical investigation 2023-12, Vol.133 (23)
Main Authors: Wang, Aiting, Huang, Haiyan, Shi, Jian-Hong, Yu, Xiaoyan, Ding, Rui, Zhang, Yuerong, Han, Qiaoqiao, Ni, Zhi-Yu, Li, Xia, Zhao, Ren, Zou, Qiang
Format: Article
Language:English
Subjects:
Colorectal cancer
Development and progression
Genetic aspects
Genetic translation
Health aspects
Homeostasis
Immune response
Immunological tolerance
Immunotherapy
Physiological aspects
RNA
Stomach cancer
Suppressor cells
T cells
Ubiquitin
Ubiquitin-proteasome system
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Summary: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 [N.sup.6]-methyladenosine ([m.sup.6]A) 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 [m.sup.6]A-based c-Myc translation efficiency. Our findings reveal that USP47 directs [m.sup.6]A-dependent metabolic programs to orchestrate Treg homeostasis and suggest novel approaches for selective immune modulation in cancer and autoimmune diseases by targeting of USP47.
ISSN:0021-9738
DOI:10.1172/JCI169365