Dynamic RBM47 ISGylation confers broad immunoprotection against lung injury and tumorigenesis via TSC22D3 downregulation
文献类型： 外文期刊
作者： Ding, Shihui 1 ; Pang, Xiquan 1 ; Luo, Shaoxiang 3 ; Gao, Huili 1 ; Li, Bo 1 ; Yue, Junqiu 1 ; Chen, Jian 1 ; Hu, Sheng 1 ; Tu, Zepeng 1 ; He, Dong 1 ; Kuang, Youyi 7 ; Dong, Zhiqiang 1 ; Zhang, Min 1 ;
作者机构： 1.Huazhong Agr Univ, Coll Life Sci & Technol, Coll Biomed & Hlth, Wuhan 430070, Peoples R China
2.Hubei Univ Med, Taihe Hosp, Ctr Neurol Dis Res, Shiyan 442000, Hubei, Peoples R China
3.Wuhan Huamei Biotech Co Ltd, Wuhan 430079, Peoples R China
4.Tongji Med Coll, Hubei Canc Hosp, Dept Pathol, Wuhan 430079, Peoples R China
5.Tongji Med Coll, Hubei Canc Hosp, Dept Head & Neck Surg, Wuhan 430079, Peoples R China
6.Tongji Med Coll, Hubei Canc Hosp, Dept Oncol, Wuhan 430079, Peoples R China
7.Chinese Acad Fishery Sci, Heilongjiang River Fisheries Res Inst, 232 Hesong St, Harbin 150070, Peoples R China
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
页码：
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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