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Autophagy programs the metabolic and functional fitness of regulatory T (T reg) cells to establish immune tolerance, yet the mechanisms governing autophagy initiation in T reg cells remain unclear. Here, we show that the E3 ubiquitin ligase ZFP91 facilitates autophagy activation to sustain T reg cell metabolic programming and functional integrity. T reg cell-specific deletion of Zfp91 caused T reg cell dysfunction and exacerbated colonic inflammation and inflammation-driven colon carcinogenesis. TCR-triggered autophagy induction largely relied on T reg cell-derived ZFP91 to restrict hyperglycolysis, which is required for the maintenance of T reg cell homeostasis. Mechanistically, ZFP91 rapidly translocated from the nucleus to the cytoplasm in response to TCR stimulation and then mediated BECN1 ubiquitination to promote BECN1-PIK3C3 complex formation. Therefore, our results highlight a ZFP91-dependent mechanism promoting TCR-initiated autophagosome maturation to maintain T reg cell homeostasis and function. © 2020 Wang et al.


Aiting Wang, Lei Ding, Zhongqiu Wu, Rui Ding, Xiao-Lu Teng, Feixiang Wang, Zhilin Hu, Lei Chen, Xiaoyan Yu, Qiang Zou. ZFP91 is required for the maintenance of regulatory T cell homeostasis and function. The Journal of experimental medicine. 2021 Feb 01;218(2)

PMID: 33355624

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