RASSF1A is required for the maintenance of nuclear actin levels
RASSF1A is required for the maintenance of nuclear actin levels
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DOI：
10.15252/embj.2018101168
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发表时间：
2019-08-15
期刊：
影响因子：
11.4
通讯作者：
O'Neill, Eric
中科院分区：
文献类型：
--
作者：
Chatzifrangkeskou, Maria;Pefani, Dafni-Eleftheria;O'Neill, Eric
核肌动蛋白参与许多重要的细胞过程，包括基因转录、染色质重塑和 mRNA 加工。肌动蛋白通过专用转运受体 importin-9 和 Exportin-6 的作用进出细胞核，但这种转运是如何调节的仍不清楚。在这里，我们证明 RASSF1A 是肌动蛋白核质运输的新型调节因子，并且是通过支持输出蛋白 6 (XPO6) 与 RAN GTPase 结合来主动维持核肌动蛋白水平所必需的。 RASSF1A（Ras 关联结构域家族 1 同工型 A）是一种肿瘤抑制基因，在所有主要实体癌中经常因启动子高甲基化而沉默。具体来说，我们证明内源性 RASSF1A 定位于核膜 (NE)，是核细胞质肌动蛋白转运和伴随调节心肌素相关转录因子 A (MRTF-A) 所必需的，MRTF-A 是转录因子血清反应因子 (SRF) 的共激活剂。 RASSF1A/RAN/XPO6/核肌动蛋白通路在癌细胞中异常，其中 RASSF1A 表达丢失，并与导致细胞粘附缺陷的 MRTF-A/SRF 活性降低相关。总之，我们发现了一种以前未知的核肌动蛋白池调节机制，并揭示了 RASSF1A 和 MRTF-A/SRF 在肿瘤抑制中以前未知的联系。
Nuclear actin participates in many essential cellular processes including gene transcription, chromatin remodelling and mRNA processing. Actin shuttles into and out the nucleus through the action of dedicated transport receptors importin-9 and exportin-6, but how this transport is regulated remains unclear. Here, we show that RASSF1A is a novel regulator of actin nucleocytoplasmic trafficking and is required for the active maintenance of nuclear actin levels through supporting binding of exportin-6 (XPO6) to RAN GTPase. RASSF1A (Ras association domain family 1 isoform A) is a tumour suppressor gene frequently silenced by promoter hypermethylation in all major solid cancers. Specifically, we demonstrate that endogenous RASSF1A localises to the nuclear envelope (NE) and is required for nucleocytoplasmic actin transport and the concomitant regulation of myocardin-related transcription factor A (MRTF-A), a co-activator of the transcription factor serum response factor (SRF). The RASSF1A/RAN/XPO6/nuclear actin pathway is aberrant in cancer cells where RASSF1A expression is lost and correlates with reduced MRTF-A/SRF activity leading to cell adhesion defects. Taken together, we have identified a previously unknown mechanism by which the nuclear actin pool is regulated and uncovered a previously unknown link of RASSF1A and MRTF-A/SRF in tumour suppression.