Dynamic RBM47 ISGylation confers broad immunoprotection against lung injury and tumorigenesis via TSC22D3 downregulation

文献类型： 外文期刊

第一作者： Ding, Shihui

作者： Ding, Shihui;Pang, Xiquan;Gao, Huili;Li, Bo;Yue, Junqiu;Chen, Jian;Hu, Sheng;Tu, Zepeng;He, Dong;Dong, Zhiqiang;Zhang, Min;Ding, Shihui;Dong, Zhiqiang;Luo, Shaoxiang;Yue, Junqiu;Chen, Jian;Hu, Sheng;Kuang, Youyi

作者机构：

期刊名称：CELL DEATH DISCOVERY （ 影响因子：7.0； 五年影响因子：6.6 ）

ISSN：

年卷期： 2023 年 9 卷 1 期

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收录情况： SCI

摘要： ISGylation is a well-established antiviral mechanism, but its specific function in immune and tissue homeostasis regulation remains elusive. Here, we reveal that the RNA-binding protein RBM47 undergoes phosphorylation-dependent ISGylation at lysine 329 to regulate immune activation and maintain lung homeostasis. K329R knockin (KI) mice with defective RBM47-ISGylation display heightened susceptibility to LPS-induced acute lung injury and lung tumorigenesis, accompanied with multifaceted immunosuppression characterized by elevated pro-inflammatory factors, reduced IFNs/related chemokines, increased myeloid-derived suppressor cells, and impaired tertiary lymphoid structures. Mechanistically, RBM47-ISGylation regulation of the expression of TSC22D3 mRNA, a glucocorticoid-inducible transcription factor, partially accounts for the effects of RBM47-ISGylation deficiency due to its broad immunosuppressive activity. We further demonstrate the direct inhibitory effect of RBM47-ISGylation on TSC22D3 expression in human cells using a nanobody-targeted E3 ligase to induce site-specific ISGylation. Furthermore, epinephrine-induced S309 phosphorylation primes RBM47-ISGylation, with epinephrine treatment exacerbating dysregulated cytokine expression and ALI induction in K329R KI mice. Our findings provide mechanistic insights into the dynamic regulation of RBM47-ISGylation in supporting immune activation and maintaining lung homeostasis.

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