Dynamic RBM47 ISGylation confers broad immunoprotection against lung injury and tumorigenesis via TSC22D3 downregulation.
Dynamic RBM47 ISGylation confers broad immunoprotection against lung injury and tumorigenesis via TSC22D3 downregulation.
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DOI：
10.1038/s41420-023-01736-z
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发表时间：
2023-11-30
影响因子：
7
通讯作者：
Zhang, Min
中科院分区：
文献类型：
--
作者：
Ding, Shihui;Pang, Xiquan;Luo, Shaoxiang;Gao, Huili;Li, Bo;Yue, Junqiu;Chen, Jian;Hu, Sheng;Tu, Zepeng;He, Dong;Kuang, Youyi;Dong, Zhiqiang;Zhang, Min
ISGylation 是一种成熟的抗病毒机制，但其在免疫和组织稳态调节中的具体功能仍然难以捉摸。在这里，我们揭示了RNA结合蛋白RBM47在赖氨酸329处经历磷酸化依赖性ISG化以调节免疫激活并维持肺稳态。 RBM47-ISGylation 有缺陷的 K329R 敲入 (KI) 小鼠对 LPS 诱导的急性肺损伤和肺肿瘤发生的易感性更高，并伴有多方面的免疫抑制，其特征是促炎因子升高、IFN/相关趋化因子减少、骨髓源性抑制细胞增加和三级淋巴结构受损。从机制上讲，RBM47-ISGylation 对 TSC22D3 mRNA（一种糖皮质激素诱导转录因子）表达的调节部分解释了 RBM47-ISGylation 缺陷由于其广泛的免疫抑制活性而产生的影响。我们使用纳米抗体靶向 E3 连接酶诱导位点特异性 ISGylation，进一步证明了 RBM47-ISGylation 对人类细胞中 TSC22D3 表达的直接抑制作用。此外，肾上腺素诱导的 S309 磷酸化引发 RBM47-ISGylation，肾上腺素治疗会加剧 K329R KI 小鼠中细胞因子表达失调和 ALI 诱导。我们的研究结果为 RBM47-ISGylation 在支持免疫激活和维持肺稳态中的动态调节提供了机制见解。
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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DOI：
10.4049/jimmunol.1600281
发表时间：
2017-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kang S;Fedoriw Y;Brenneman EK;Truong YK;Kikly K;Vilen BJ
通讯作者：
Vilen BJ
宇宙（癌症中的体细胞突变目录）数据库和网站。
影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
5.7
作者：
Esposito, Emanuela;Bruscoli, Stefano;Riccardi, Carlo
通讯作者：
Riccardi, Carlo
影响因子：
9.7
作者：
BERTRAM, JS;JANIK, P
通讯作者：
JANIK, P
影响因子：
4.6
作者：
Han JH;Suh CH;Jung JY;Ahn MH;Han MH;Kwon JE;Yim H;Kim HA
通讯作者：
Kim HA