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An ARF6-Exportin-5 axis delivers pre-miRNA cargo to tumour microvesicles.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2019-06-24 , DOI: 10.1038/s41556-019-0345-y
James W Clancy 1 , Ye Zhang 1 , Colin Sheehan 1 , Crislyn D'Souza-Schorey 1
Nature Cell Biology ( IF 17.3 ) Pub Date : 2019-06-24 , DOI: 10.1038/s41556-019-0345-y
James W Clancy 1 , Ye Zhang 1 , Colin Sheehan 1 , Crislyn D'Souza-Schorey 1
Affiliation
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Tumour-derived microvesicles (TMVs) comprise a class of extracellular vesicles released from tumour cells that are now understood to facilitate communication between the tumour and the surrounding microenvironment. Despite their significance, the regulatory mechanisms governing the trafficking of bioactive cargos to TMVs at the cell surface remain poorly defined. Here we describe a molecular pathway for the delivery of microRNA (miRNA) cargo to nascent TMVs involving the dissociation of a pre-miRNA/Exportin-5 complex from Ran-GTP following nuclear export and its subsequent transfer to a cytoplasmic shuttle comprised of ARF6-GTP and GRP1. As such, ARF6 activation increases the pre-miRNA cargo contained within TMVs through a process that requires the casein kinase 2-mediated phosphorylation of RanGAP1. Furthermore, TMVs were found to contain pre-miRNA processing machinery including Dicer and Argonaute-2, which allow for cell-free pre-miRNA processing within shed vesicles. These findings offer cellular targets to block the loading and processing of pre-miRNAs within TMVs.
中文翻译：
ARF6-Exportin-5轴可将pre-miRNA货物运送至肿瘤微泡。
源自肿瘤的微囊泡（TMV）包括一类从肿瘤细胞释放的细胞外囊泡，现已被理解为促进肿瘤与周围微环境之间的通讯。尽管它们具有重要意义，但在细胞表面控制生物活性货物向TMV的运输的调控机制仍然不明确。在这里，我们描述了将microRNA（miRNA）货物运送至新生TMV的分子途径，涉及核出口后Ran-GTP的pre-miRNA / Exportin-5复合物的解离，以及随后转移至包含ARF6的胞质穿梭物GTP和GRP1。这样，ARF6激活通过需要酪蛋白激酶2介导的RanGAP1磷酸化的过程增加了TMV中包含的pre-miRNA货物。此外，发现TMV包含pre-miRNA加工机器，包括Dicer和Argonaute-2，它们可在脱落的囊泡中进行无细胞的pre-miRNA加工。这些发现为阻断TMV中pre-miRNA的装载和加工提供了细胞靶点。
更新日期：2019-06-24
中文翻译：
ARF6-Exportin-5轴可将pre-miRNA货物运送至肿瘤微泡。
源自肿瘤的微囊泡（TMV）包括一类从肿瘤细胞释放的细胞外囊泡，现已被理解为促进肿瘤与周围微环境之间的通讯。尽管它们具有重要意义，但在细胞表面控制生物活性货物向TMV的运输的调控机制仍然不明确。在这里，我们描述了将microRNA（miRNA）货物运送至新生TMV的分子途径，涉及核出口后Ran-GTP的pre-miRNA / Exportin-5复合物的解离，以及随后转移至包含ARF6的胞质穿梭物GTP和GRP1。这样，ARF6激活通过需要酪蛋白激酶2介导的RanGAP1磷酸化的过程增加了TMV中包含的pre-miRNA货物。此外，发现TMV包含pre-miRNA加工机器，包括Dicer和Argonaute-2，它们可在脱落的囊泡中进行无细胞的pre-miRNA加工。这些发现为阻断TMV中pre-miRNA的装载和加工提供了细胞靶点。
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