Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China.
Cell Death Dis. 2020 Apr 17;11(4):242. doi: 10.1038/s41419-020-2436-x.
Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer, and the identification of the apoptotic process of NSCLC is vital for its treatment. Usually, both the expression level and the cell surface level of TNFRSF10B (TNF Receptor superfamily member 10B) will increase after treatment with some chemotherapeutic agents, which plays a critical role in the apoptosis induction. However, the exact molecular mechanism underlying TNFRSF10B regulation remains largely elusive. Here, we found that TNFRSF10B, along with a vesicular trafficking regulator protein, YIPF2, were upregulated after treatment with pemetrexed (PEM) in NSCLC cells. Besides, YIPF2 increased the surface level of TNFRF10B, while YIPF2 knockdown inhibited the upregulation of TNFRSF10B and its recycling to plasma membrane. In addition, RAB8 decreased the cell surface TNFRSF10B by promoting its removing from plasma membrane to cytoplasm. Furthermore, we found that YIPF2, RAB8 and TNFRSF10B proteins interacted physically with each other. YIPF2 could further inhibit the physical interaction between TNFRSF10B and RAB8, thereby suppressing the removing of TNFRSF10B from plasma membrane to cytoplasm mediated by RAB8 and maintaining its high level on cell surface. Finally, using bioinformatics database, the YIPF2-TNFRSF10B axis was confirmed to be associated with the malignant progression of lung cancer. Taken together, we show that YIPF2 promotes chemotherapeutic agent-mediated apoptosis via enhancing TNFRSF10B recycling to plasma membrane in NSCLC cells. These findings may be beneficial for the development of potential prognostic markers of NSCLC and may provide effective treatment strategy.
非小细胞肺癌（NSCLC）是最常见的肺癌组织学类型，鉴定 NSCLC 的凋亡过程对其治疗至关重要。通常，在某些化疗药物治疗后，TNFRSF10B（肿瘤坏死因子受体超家族成员 10B）的表达水平和细胞表面水平都会升高，这在诱导细胞凋亡中起着关键作用。然而，TNFRSF10B 调节的确切分子机制在很大程度上仍不清楚。在这里，我们发现 TNFRSF10B 与一种囊泡运输调节剂蛋白 YIPF2 在 NSCLC 细胞用培美曲塞（PEM）治疗后上调。此外，YIPF2 增加了 TNFRSF10B 的表面水平，而 YIPF2 敲低抑制了 TNFRSF10B 的上调及其向质膜的再循环。此外，RAB8 通过促进 TNFRSF10B 从质膜到细胞质的去除，减少细胞表面 TNFRSF10B。此外，我们发现 YIPF2、RAB8 和 TNFRSF10B 蛋白相互物理作用。YIPF2 可以进一步抑制 TNFRSF10B 和 RAB8 之间的物理相互作用，从而抑制 RAB8 介导的 TNFRSF10B 从质膜到细胞质的去除，并维持其在细胞表面的高水平。最后，使用生物信息学数据库，证实了 YIPF2-TNFRSF10B 轴与肺癌的恶性进展有关。总之，我们表明 YIPF2 通过增强 TNFRSF10B 向质膜的再循环来促进化疗药物介导的 NSCLC 细胞凋亡。这些发现可能有助于 NSCLC 潜在预后标志物的开发，并为提供有效的治疗策略提供了依据。
