TNKS1BP1 通过抑制 EEF2 降解介导 AECII 衰老和辐射诱导的肺损伤。

IF 5.8 2区医学 Q1 Medicine

Respiratory Research Pub Date : 2024-08-07 DOI:10.1186/s12931-024-02914-y

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

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引用次数: 0

摘要

背景：尽管最近的研究对辐射诱导肺损伤（RILI）的发病机制有了机理上的了解，但很少有治疗方法显示出治疗这种疾病的确切前景。II型肺泡上皮细胞（AECII）以各种方式损伤，导致炎症反应，从而引发RILI：结果：我们在此报告了辐射（IR）上调 TNKS1BP1，通过上调 EEF2 导致 RILI 小鼠肺泡上皮细胞和肺组织中的细胞衰老逐渐累积。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，促进RILI的发展。在对红外的反应中，TNKS1BP1的升高与CNOT4相互作用并降低了CNOT4，从而抑制了EEF2的降解。EEF2的异位表达加速了AECII的衰老。利用 TNKS1BP1 基因敲除（KO）小鼠模型系统，我们证明 TNKS1BP1 基因敲除可预防 IR 诱导的肺组织衰老和 RILI：值得注意的是，这项研究表明 TNKS1BP1/CNOT4/EEF2 轴在 AECII 衰老中的调控机制可能是治疗 RILI 的潜在策略。

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

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.

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来源期刊

Respiratory Research RESPIRATORY SYSTEM-

CiteScore

9.70

自引率

1.70%

发文量

314

审稿时长

4-8 weeks

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.