Abstract
STAT1 is a master regulator that orchestrates type 1 and 2 interferon (IFN)-induced IFN-stimulated gene (ISG) expression. The mechanisms by which STAT1 is phosphorylated and activated upon IFN signaling remain elusive. Our work demonstrated that ubiquitination of STAT1 mediated by the E3 ligase RNF220 contributed significantly to STAT1 activation and innate immune responses. Rnf220 gene deficiency resulted in the downregulation of IFN signaling and decreased expression of ISGs in response to type 1 and 2 IFNs stimulation and Acinetobacter baumannii and HSV-1 infection. Mechanistically, RNF220 interacted with STAT1 and mediated the K63-linked polyubiquitination of STAT1 at residue K110, which promoted the interaction between STAT1 and the kinase JAK1. The expression of RNF220 was induced by pathogenic infection and IFN signaling. RNF220 promoted STAT1 ubiquitination and phosphorylation through a positive feedback loop. RNF220 haploinsufficiency impaired IFN signaling, and RNF220-defective mice were more susceptible to A. baumannii and HSV-1 infection than WT mice. Our work offers novel insights into the mechanisms of STAT1 modulation and provides potential therapeutic targets against bacterial and viral infection and inflammatory diseases.
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Acknowledgements
We thank C. Gao (Shandong University School of Basic Medical Sciences, Jinan) for mutated Stat1 plasmids; X. Cao (Nankai University, Tianjin) for Stat1–/– L929 cells; C. Chen (Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming) for ubiquitin plasmids; J. Zhou (Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming) for HSV-1; S.-Z. Duan (Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai) for L929 cells. This work was supported by the National Key Research and Development Program of China (2017YFD0500300), the Chinese Academy of Sciences (XDB13000000 and HXDTZX-2019-1), the National Natural Science Foundation of China (31970896, 31871483, 31671521, 31500847, 31701134, and 81701578) and Yunnan Province (2019FJ008, 2018FA038, 2018FB127, 2018FB131, HXDT-2019-2, and AMHD-2018-2).
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XQ and BM designed the study; XG, PM, YL, YY, CW, TX, HW, CL, BM, and XQ performed experiments and analyzed the data; XQ wrote the manuscript.
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Guo, X., Ma, P., Li, Y. et al. RNF220 mediates K63-linked polyubiquitination of STAT1 and promotes host defense. Cell Death Differ 28, 640–656 (2021). https://doi.org/10.1038/s41418-020-00609-7
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DOI: https://doi.org/10.1038/s41418-020-00609-7
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