TRAIL 诱导 TRAIL 死亡受体的核易位和染色质定位,Cancers

当前位置： X-MOL 学术 › Cancers › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

TRAIL 诱导 TRAIL 死亡受体的核易位和染色质定位
Cancers ( IF 4.5 ) Pub Date : 2019-08-14 , DOI: 10.3390/cancers11081167
Ufuk Mert ₁ , Alshaimaa Adawy ₁ , Elisabeth Scharff ₁ , Pierre Teichmann ₁ , Anna Willms ₁ , Verena Haselmann ₂ , Cynthia Colmorgen ₁ , Johannes Lemke ₃ , Silvia von Karstedt _{4,

5} , Jürgen Fritsch ₆ , Anna Trauzold ₁

Affiliation

肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 与质膜 TRAIL-R1/-R2 的结合选择性地杀死肿瘤细胞。这一发现导致评估 TRAIL-R1/-R2 作为抗癌治疗的靶点，但相应的临床试验令人失望。同时，发现许多癌细胞具有 TRAIL 抗性，并且 TRAIL-R1/-R2 触发可能导致肿瘤促进作用。有趣的是，最近的研究揭示了长期被忽视的细胞内 TRAIL-R1/-R2 的特定功能，其中核 (n)TRAIL-R2 的促肿瘤功能是 let-7-成熟的调节剂。由于 TRAIL-Rs 的核贩卖还不是很清楚，我们在目前的研究中解决了这个问题。细胞表面生物素化和细胞内隔室中生物素化蛋白质的跟踪表明 nTRAIL-Rs 源自质膜。核 TRAIL-Rs 运输是一个快速过程，需要网格蛋白依赖性内吞作用，并且它是 TRAIL 依赖性的。免疫沉淀和免疫荧光方法揭示了 nTRAIL-R2 与核质穿梭蛋白 Exportin-1/CRM-1 的相互作用。TRAIL-R2 中推定的核输出序列 (NES) 的突变或 Leptomycin-B 对 CRM-1 的抑制导致 TRAIL-R2 的核积累。此外，TRAIL-R1 和 TRAIL-R2 组成型定位于染色质，TRAIL 处理强烈增强了染色质。我们的数据突出了表面活化的 TRAIL-Rs 通过直接运输和信号进入细胞核的新作用，

"点击查看英文标题和摘要"

TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors

Binding of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to the plasma membrane TRAIL-R1/-R2 selectively kills tumor cells. This discovery led to evaluation of TRAIL-R1/-R2 as targets for anti-cancer therapy, yet the corresponding clinical trials were disappointing. Meanwhile, it emerged that many cancer cells are TRAIL-resistant and that TRAIL-R1/-R2-triggering may lead to tumor-promoting effects. Intriguingly, recent studies uncovered specific functions of long ignored intracellular TRAIL-R1/-R2, with tumor-promoting functions of nuclear (n)TRAIL-R2 as the regulator of let-7-maturation. As nuclear trafficking of TRAIL-Rs is not well understood, we addressed this issue in our present study. Cell surface biotinylation and tracking of biotinylated proteins in intracellular compartments revealed that nTRAIL-Rs originate from the plasma membrane. Nuclear TRAIL-Rs-trafficking is a fast process, requiring clathrin-dependent endocytosis and it is TRAIL-dependent. Immunoprecipitation and immunofluorescence approaches revealed an interaction of nTRAIL-R2 with the nucleo-cytoplasmic shuttle protein Exportin-1/CRM-1. Mutation of a putative nuclear export sequence (NES) in TRAIL-R2 or the inhibition of CRM-1 by Leptomycin-B resulted in the nuclear accumulation of TRAIL-R2. In addition, TRAIL-R1 and TRAIL-R2 constitutively localize to chromatin, which is strongly enhanced by TRAIL-treatment. Our data highlight the novel role for surface-activated TRAIL-Rs by direct trafficking and signaling into the nucleus, a previously unknown signaling principle for cell surface receptors that belong to the TNF-superfamily.

更新日期：2019-08-14

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南