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.
ZFP91 is required for the maintenance of regulatory T cell homeostasis and function
Disclosures: The authors declare no competing interests exist.
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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. J Exp Med 1 February 2021; 218 (2): e20201217. doi: https://doi.org/10.1084/jem.20201217
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