TNKS1BP1通过抑制EEF2降解介导II型肺泡上皮细胞衰老和辐射诱导的肺损伤。

TNKS1BP1 mediates AECII senescence and radiation induced lung injury through suppressing EEF2 degradation.

作者信息

Zhu Jiaojiao, Ao Xingkun, Liu Yuhao, Zhou Shenghui, Hou Yifan, Yan Ziyan, Zhou Lin, Chen Huixi, Wang Ping, Liang Xinxin, Xie Dafei, Gao Shanshan, Zhou Ping-Kun, Gu Yongqing

机构信息

Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, China.

Hengyang Medical College, University of South China, Hengyang, 421001, China.

出版信息

Respir Res. 2024 Aug 7;25(1):299. doi: 10.1186/s12931-024-02914-y.

DOI:10.1186/s12931-024-02914-y

PMID:39113018

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11308570/

Abstract

BACKGROUND

Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI.

RESULTS

Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI.

CONCLUSIONS

Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.

摘要

背景

尽管近期研究对辐射诱导的肺损伤（RILI）的发病机制提供了机制性理解，但很少有治疗方法显示出治疗这种疾病的确切前景。以各种方式损伤II型肺泡上皮细胞（AECII）会引发炎症反应，从而启动RILI。

结果

在此，我们报告辐射（IR）上调TNKS1BP1，通过上调RILI小鼠AECII和肺组织中的EEF2导致细胞衰老的逐步积累。衰老的AECII诱导衰老相关分泌表型（SASP），从而激活成纤维细胞和巨噬细胞以促进RILI的发展。响应IR，升高的TNKS1BP1与CNOT4相互作用并降低其水平，从而抑制EEF2的降解。EEF2的异位表达加速了AECII衰老。使用TNKS1BP1基因敲除（KO）小鼠的模型系统，我们证明TNKS1BP1基因敲除可预防IR诱导的肺组织衰老和RILI。