PDF(Pubmed)
Abstract：
TMEM173 is a pattern recognition receptor detecting cytoplasmic nucleic acids and transmits cGAS related signals that activate host innate immune responses. It has also been found to be involved in tumor immunity and tumorigenesis. In this study, we first identified that the FKBP4/NR3C1 axis was a novel negative regulator of TMEM173 in human breast cancer (BC) cells. The effect of FKBP4 appeared to be at the transcriptional level of TMEM173, because it could suppress the promoter activity of TMEM173, thereby affecting TMEM173 at mRNA and protein levels. Past studies, our bioinformatics analysis, and in vitro experiments further implied that FKBP4 regulated TMEM173 via regulating nuclear translocation of NR3C1. We then demonstrated that the FKBP4/NR3C1/TMEM173 signaling pathway could regulate autophagy and proliferation of BC cells as well as dendritic cell (DC) abundance through exosome release. Our study found an unprecedented strategy used by BC to escape from TMEM173 mediated tumor suppression. Identification of the FKBP4/NR3C1 axis as a novel TMEM173 regulator would provide insights for novel anti-tumor strategy against BC among tumor microenvironment.
摘要：
TMEM173是检测细胞质核酸的模式识别受体,并传递激活宿主先天免疫应答的cGAS相关信号。还发现它与肿瘤免疫和肿瘤发生有关。在这项研究中,我们首先发现FKBP4/NR3C1轴是人乳腺癌（BC）细胞中TMEM173的新型负调节因子。FKBP4的作用似乎在TMEM173的转录水平上，因为它可以抑制TMEM173的启动子活性，从而在mRNA和蛋白质水平上影响TMEM173。过去的研究，我们的生物信息学分析，体外实验进一步暗示FKBP4通过调节NR3C1的核易位来调节TMEM173。然后，我们证明了FKBP4/NR3C1/TMEM173信号通路可以通过外泌体释放调节BC细胞以及树突状细胞（DC）的自噬和增殖。我们的研究发现，BC使用了一种前所未有的策略来逃避TMEM173介导的肿瘤抑制。将FKBP4/NR3C1轴鉴定为新型TMEM173调节因子将为肿瘤微环境中针对BC的新型抗肿瘤策略提供见解。
