PLK1/vimentin signaling facilitates immune escape by recruiting Smad2/3 to PD-L1 promoter in metastatic lung adenocarcinoma.
PLK1/vimentin signaling facilitates immune escape by recruiting Smad2/3 to PD-L1 promoter in metastatic lung adenocarcinoma.
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DOI：
10.1038/s41418-021-00781-4
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发表时间：
2021-09
影响因子：
12.4
通讯作者：
Yim H
中科院分区：
文献类型：
--
作者：
Jang HR;Shin SB;Kim CH;Won JY;Xu R;Kim DE;Yim H
波形蛋白在上皮-间质转化（EMT）中的必要功能尚不清楚。在这里，我们发现PLK 1磷酸化的波形蛋白触发TGF-β信号传导，从而导致肺腺癌的转移和PD-L1表达，从而抑制免疫。Vimentin和PLK 1的表达与肺腺癌患者的总生存率之间存在显著的临床相关性，而与肺鳞癌患者的总生存率之间无相关性。在TGF-β诱导的肺腺癌EMT过程中，波形蛋白磷酸化伴随着PLK 1的激活。在通过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，在3D细胞培养和尾静脉注射转移模型中，与野生型和其他版本相比，S339处的磷酸化显示出最有效的转移和肿瘤发生，具有最高的PD-L1表达。在S339处的拟磷酸波形蛋白与p-Smad 2相互作用以使其核定位，从而导致PD-L1的表达。Vim、PLK 1和CD 274在原发性和转移性肺腺癌中的表达与患者的生存率呈负相关。因此，PLK 1介导的波形蛋白磷酸化激活TGF-β信号通路，通过表达PD-L1导致肺腺癌的转移和免疫逃逸，PD-L1在肺腺癌中起穿梭蛋白的作用。
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.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
DOI：
10.1038/labinvest.2017.104
发表时间：
2018-03
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
Khan I;Steeg PS
通讯作者：
Steeg PS
DOI：
10.1083/jcb.134.4.971
发表时间：
1996-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Goldman RD;Khuon S;Chou YH;Opal P;Steinert PM
通讯作者：
Steinert PM
影响因子：
5.6
作者：
Meier, Markus;Padilla, G. Pauline;Burkhard, Peter
通讯作者：
Burkhard, Peter
影响因子：
4.8
作者：
Mendez, Melissa G.;Kojima, Shin-Ichiro;Goldman, Robert D.
通讯作者：
Goldman, Robert D.