Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway.
Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway.
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DOI：
10.1126/scisignal.aar5401
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发表时间：
2018-07-03
影响因子：
7.3
通讯作者：
Jackson SP
中科院分区：
文献类型：
--
作者：
Larrieu D;Viré E;Robson S;Breusegem SY;Kouzarides T;Jackson SP
Hutchinson-Gilford progeria syndrome（HGPS）是一种无法治愈的早衰症。因此，识别HGPS中失调的生物学过程可能有助于确定新的治疗策略。来自HGPS患者的成纤维细胞显示小GTP酶Ran（RanGTP）的GTP结合形式的核质穿梭缺陷，这导致蛋白质异常转运到细胞核中。我们报告说，微管在HGPS细胞中的稳定隔离的非经典的核输入蛋白转运蛋白-1（TNPO 1）在细胞质中，从而影响其货物，包括核孔蛋白NUP 153的核定位。因此，核Ran、核孔蛋白TPR的核锚定和染色质组织被破坏，解除基因表达的调节并诱导衰老。抑制N-乙酰转移酶10（NAT 10）通过重新平衡TNPO 1的核质比改善HGPS表型。这恢复了核孔复合物的完整性和核Ran定位，从而纠正了HGPS细胞表型。我们在健康老年人的细胞中观察到了类似的机制。这项研究确定了衰老中受影响的核输入途径，并强调了抑制NAT 10作为HGPS以及与正常衰老相关的病理学的可能治疗策略的潜力。
Hutchinson-Gilford progeria syndrome (HGPS) is an incurable premature aging disease. Identifying deregulated biological processes in HGPS might thus help define novel therapeutic strategies. Fibroblasts from HGPS patients display defects in nucleocytoplasmic shuttling of the GTP-bound form of the small GTPase Ran (RanGTP), which leads to abnormal transport of proteins into the nucleus. We report that microtubule stabilization in HGPS cells sequestered the nonclassical nuclear import protein Transportin-1 (TNPO1) in the cytoplasm, thus affecting the nuclear localization of its cargo, including the nuclear pore protein NUP153. Consequently, nuclear Ran, nuclear anchorage of the nucleoporin TPR, and chromatin organization were disrupted, deregulating gene expression and inducing senescence. Inhibiting N-acetyltransferase 10 (NAT10) ameliorated HGPS phenotypes by rebalancing the nuclear to cytoplasmic ratio of TNPO1. This restored nuclear pore complex integrity and nuclear Ran localization, thereby correcting HGPS cellular phenotypes. We observed a similar mechanism in cells from healthy aged individuals. This study identifies a nuclear import pathway affected in aging and underscores the potential for NAT10 inhibition as a possible therapeutic strategy for HGPS and perhaps also for pathologies associated with normal aging.
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影响因子：
3.3
作者：
Datta S;Snow CJ;Paschal BM
通讯作者：
Paschal BM
DOI：
10.18632/aging.100717
发表时间：
2015-01
期刊：
Aging
影响因子：
--
作者：
Aliper AM;Csoka AB;Buzdin A;Jetka T;Roumiantsev S;Moskalev A;Zhavoronkov A
通讯作者：
Zhavoronkov A
影响因子：
46.9
作者：
Fredriksson, S;Gullberg, M;Landegren, U
通讯作者：
Landegren, U
影响因子：
37.8
作者：
Gordon LB;Massaro J;D'Agostino RB Sr;Campbell SE;Brazier J;Brown WT;Kleinman ME;Kieran MW;Progeria Clinical Trials Collaborative
通讯作者：
Progeria Clinical Trials Collaborative
影响因子：
5.6
作者：
Jean-Philippe J;Paz S;Caputi M
通讯作者：
Caputi M