TRIM59 在肺动脉高压中的作用：调节蛋白质泛素化修饰。
A role of TRIM59 in pulmonary hypertension: modulating the protein ubiquitylation modification.
机构信息
Department of Pulmonary and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, People's Republic of China.
Academy of Medical Science, Zhengzhou University, Zhengzhou, People's Republic of China.
出版信息
J Transl Med. 2023 Nov 17;21(1):821. doi: 10.1186/s12967-023-04712-4.
BACKGROUND
Pulmonary hypertension (PH), an infrequent disease, is characterized by excessive pulmonary vascular remodeling and proliferation of pulmonary artery smooth muscle cells (PASMCs). However, its underlying molecular mechanisms remain unclear. Uncovering its molecular mechanisms will be beneficial to the treatment of PH.
METHODS
Differently expressed genes (DEGs) in the lung tissues of PH patients were analyzed with a GEO dataset GSE113439. From these DEGs, we focused on TRIM59 which was highly expressed in PH patients. Subsequently, the expression of TRIM59 in the pulmonary arteries of PH patients, lung tissues of PH rat model and PASMCs cultured in a hypoxic condition was verified by quantitative real-time PCR (qPCR), western blot and immunohistochemistry. Furthermore, the role of TRIM59 in PAMSC proliferation and pathological changes in PH rats was assessed via gain-of-function and loss-of-function experiments. In addition, the transcriptional regulation of YAP1/TEAD4 on TRIM59 was confirmed by qPCR, western blot, luciferase reporter assay, ChIP and DNA pull-down. In order to uncover the underlying mechanisms of TRIM59, a protein ubiquitomics and a CoIP- HPLC-MS/MS were companied to identify the direct targets of TRIM59.
RESULTS
TRIM59 was highly expressed in the pulmonary arteries of PH patients and lung tissues of PH rats. Over-expression of TRIM59 accelerated the proliferation of PASMCs, while TRIM59 silencing resulted in the opposite results. Moreover, TRIM59 silencing mitigated the injuries in heart and lung and attenuated pulmonary vascular remodeling during PH. In addition, its transcription was positively regulated by YAP1/TEAD4. Then we further explored the underlying mechanisms of TRIM59 and found that TRIM59 overexpression resulted in an altered ubiquitylation of proteins. Accompanied with the results of CoIP- HPLC-MS/MS, 34 proteins were identified as the direct targets of TRIM59.
CONCLUSION
TRIM59 was highly expressed in PH patients and promoted the proliferation of PASMCs and pulmonary vascular remodeling, thus contributing to the pathogenesis of PH. It is indicated that TRIM59 may become a potential target for PH treatment.
背景
肺动脉高压（PH）是一种罕见的疾病，其特征为肺血管过度重塑和肺动脉平滑肌细胞（PASMCs）增生。然而，其潜在的分子机制尚不清楚。揭示其分子机制将有助于 PH 的治疗。
方法
利用 GEO 数据集 GSE113439 分析 PH 患者肺组织中的差异表达基因（DEGs）。从这些 DEGs 中，我们重点关注在 PH 患者中高表达的 TRIM59。随后，通过定量实时 PCR（qPCR）、western blot 和免疫组织化学验证了 TRIM59 在 PH 患者的肺动脉、PH 大鼠模型的肺组织和低氧培养的 PASMCs 中的表达。此外，通过功能获得和功能丧失实验评估了 TRIM59 在 PASMC 增殖和 PH 大鼠病理变化中的作用。另外，通过 qPCR、western blot、荧光素酶报告实验、ChIP 和 DNA 下拉实验证实了 YAP1/TEAD4 对 TRIM59 的转录调控。为了揭示 TRIM59 的潜在机制，进行了蛋白质泛素组学和 CoIP-HPLC-MS/MS 以鉴定 TRIM59 的直接靶标。
结果
TRIM59 在 PH 患者的肺动脉和 PH 大鼠的肺组织中高表达。TRIM59 的过表达加速了 PASMC 的增殖，而 TRIM59 的沉默则产生相反的结果。此外，TRIM59 的沉默减轻了 PH 期间心脏和肺部的损伤，并减弱了肺血管重塑。此外，其转录受 YAP1/TEAD4 正向调控。然后，我们进一步探讨了 TRIM59 的潜在机制，发现 TRIM59 的过表达导致蛋白质的泛素化发生改变。伴随着 CoIP-HPLC-MS/MS 的结果，鉴定出 34 种蛋白为 TRIM59 的直接靶标。
结论
TRIM59 在 PH 患者中高表达，并促进 PASMC 的增殖和肺血管重塑，从而导致 PH 的发病机制。这表明 TRIM59 可能成为 PH 治疗的潜在靶点。
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