Nucleocytoplasmic shuttling of SAMHD1 is important for LINE-1 suppression
Nucleocytoplasmic shuttling of SAMHD1 is important for LINE-1 suppression
复制标题
SAMHD1 的核质穿梭对于 LINE-1 抑制很重要
DOI：
10.1016/j.bbrc.2019.02.009
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发表时间：
2019-03-19
影响因子：
3.1
通讯作者：
Zhao, Ke
中科院分区：
文献类型：
--
作者：
Du, Juan;Peng, Yanfeng;Zhao, Ke
目前，SAMHD1是人类细胞中唯一已知的DNTPase。它还抑制了逆转录病毒和恢复元件的复制。 SAMHD1包含经典的核定位序列（NLS），并驻留在活细胞或固定细胞中的细胞核中。据报道，NLS的改变或去除不会影响SAMHD1的DNTPase或抗病毒活性。但是，目前尚不清楚核定位是否参与了SAMHD1介导的抑制，例如散布的元素1型（线1或L1）。在这项研究中，我们报道了SAMHD1是一种核细胞型式蛋白质。基于Digitonin的细胞质/细胞核分级测试表明，SAMHD1能够从细胞核中导出，通过在活细胞中引入外源性Exportin XPO1证实。有趣的是，通过突变或去除NLS来改变蛋白质的亚细胞定位，从而显着提高了SAMHD1在L1抑制中的效力。对SAMHD1突变体的进一步测试表明，核质班次穿梭对SAMHD1介导的L1抑制很重要。最后，我们证明了SAMHD1的细胞质分布导致L1 ORF2P的耗竭增强。综上所述，我们的数据揭示了SAMHD1是一种核细胞的穿梭蛋白，并将SAMHD1的这种新特征与反对L1逆转录的效力相关联，这为对SAMHD1及其在L1抑制中的作用提供了更多见解。 （c）2019 Elsevier Inc.保留所有权利。
Currently, SAMHD1 is the only known dNTPase in human cells. It also suppresses the replication of both retroviruses and retroelements. SAMHD1 contains a classic nuclear localization sequence (NLS) and resides in the nucleus in live or fixed cells. It has been reported that alteration or removal of NLS does not affect the dNTPase or the antiviral activity of SAMHD1. However, it was unclear whether the nuclear localization was involved in SAMHD1-mediated suppression against retroelements such as long interspersed element type 1 (LINE-1 or L1). In this study, we reported that SAMHD1 is a nucleocytoplasmic shuttling protein. Digitonin-based cytoplasm/nucleus fractionation tests suggested that SAMHD1 is capable of being exported from the nucleus, which was confirmed by introducing exogenous exportin Xpo1 in live cells. Interestingly, altering the protein's subcellular localization by mutating or removing NLS significantly enhances SAMHD1's potency in L1 suppression. Further tests with SAMHD1 mutants indicated that nucleocytoplasmic shuttling is important for SAMHD1-mediated L1 suppression. Finally, we demonstrated that the cytoplasmic distribution of SAMHD1 leads to an enhanced depletion of L1 ORF2p. Taken together, our data have revealed SAMHD1 as a nucleocytoplasmic shuttling protein, and associated such a new feature of SAMHD1 with its potency against L1 retrotransposition, which provides more insights to the understanding of SAMHD1 and its role in L1 suppression. (C) 2019 Elsevier Inc. All rights reserved.