Research ArticlePREMATURE AGING

Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway

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Sci. Signal.  03 Jul 2018:
Vol. 11, Issue 537, eaar5401
DOI: 10.1126/scisignal.aar5401

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Rescuing premature aging

Cells from patients with Hutchinson-Gilford progeria syndrome (HGPS) have defects in nuclear architecture and function that lead to premature cellular senescence, aging, and early death. Larrieu et al. (see the Focus by Wilson) found that inhibition or depletion of the acetyltransferase NAT10 rescued many of the phenotypes of HGPS patient cells by destabilizing microtubules, which reversed the abnormal cytoplasmic accumulation of the nuclear importer Transportin-1 (TNPO1). This restored proper assembly of the nuclear pore complex, import of nuclear proteins, chromatin organization, and gene expression patterns. Together, these effects delayed the premature senescence of HGPS cells. Cells from aged individuals also showed cytoplasmic retention of TNPO1, suggesting that targeting NAT10 might be a clinical strategy for treating both HGPS and age-related pathologies.

Abstract

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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