Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do, Korea.
Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, Korea.
Cell Death Differ. 2021 Sep;28(9):2745-2764. doi: 10.1038/s41418-021-00781-4. Epub 2021 May 7.
The prerequisite function of vimentin for the epithelial-mesenchymal transition (EMT) is not clearly elucidated yet. Here, we show that vimentin phosphorylated by PLK1, triggers TGF-β-signaling, which consequently leads to metastasis and PD-L1 expression for immune suppression in lung adenocarcinoma. The clinical correlation between expression of both vimentin and PLK1, and overall survival rates of patients was significant in lung adenocarcinoma but not in squamous cell carcinoma. The phosphorylation of vimentin was accompanied by the activation of PLK1 during TGF-β-induced EMT in lung adenocarcinoma. Among the several phosphorylation sites determined by phospho-proteomic analysis and the site-specific mutagenesis, the phosphorylation at S339 displayed the most effective metastasis and tumourigenesis with the highest expression of PD-L1, compared with that of wild-type and other versions in both 3D cell culture and tail-vein injection metastasis models. Phosphomimetic vimentin at S339 interacted with p-Smad2 for its nuclear localization, leading to the expression of PD-L1. Clinical relevance revealed the inverse correlation between the survival rates of patients and the expressions of VIM, PLK1, and CD274 in primary and metastatic lung adenocarcinoma. Thus, PLK1-mediated phosphorylation of vimentin activates TGF-β signaling pathway, leading to the metastasis and immune escape through the expression of PD-L1, functioning as a shuttling protein in lung adenocarcinoma.
波形蛋白（vimentin）在 EMT 中发挥上皮-间质转化的前提功能尚未得到明确阐明。在这里，我们发现 PLK1 磷酸化的波形蛋白可触发 TGF-β 信号通路，进而导致肺腺癌转移和 PD-L1 表达以抑制免疫。在肺腺癌中，波形蛋白和 PLK1 的表达与患者的总生存率之间存在显著的临床相关性，但在鳞状细胞癌中则没有。在 TGF-β 诱导的肺腺癌细胞 EMT 过程中，波形蛋白的磷酸化伴随着 PLK1 的激活。在磷酸化蛋白质组学分析和位点特异性突变确定的几个磷酸化位点中，与野生型和其他版本相比，S339 位点的磷酸化在 3D 细胞培养和尾静脉注射转移模型中表现出最有效的转移和肿瘤发生能力，以及最高的 PD-L1 表达。S339 位点的磷酸化波形蛋白与 p-Smad2 相互作用，使其核定位，从而导致 PD-L1 的表达。临床相关性揭示了原发性和转移性肺腺癌中患者生存率与 VIM、PLK1 和 CD274 表达之间的负相关。因此，PLK1 介导的波形蛋白磷酸化激活 TGF-β 信号通路，通过 PD-L1 的表达导致转移和免疫逃避，在肺腺癌中作为穿梭蛋白发挥作用。
