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

• Published in: Science signaling 2018-07, Vol.11 (537)
• Main Authors: Larrieu, Delphine, Viré, Emmanuelle, Robson, Samuel, Breusegem, Sophia Y, Kouzarides, Tony, Jackson, Stephen P
• Format: Article
• Language: English
• Subjects: Acetyltransferase; Active Transport, Cell Nucleus; Adult; Aged, 80 and over; Aging; beta Karyopherins - genetics; beta Karyopherins - metabolism; Biological activity; Case-Control Studies; Cell Nucleus - metabolism; Cells, Cultured; Cellular Senescence; Child; Chromatin; Cytoplasm; Defects; Deregulation; Female; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gene expression; Guanosine triphosphatases; Guanosine triphosphate; Humans; Imports; Inhibition; Localization; Male; Microtubules; Microtubules - metabolism; Microtubules - pathology; N-Acetyltransferase; N-Terminal Acetyltransferase E - antagonists & inhibitors; N-Terminal Acetyltransferase E - genetics; N-Terminal Acetyltransferase E - metabolism; N-Terminal Acetyltransferases; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Nuclear transport; Nuclei (cytology); Patients; Phenotype; Phenotypes; Progeria; Progeria - genetics; Progeria - metabolism; Progeria - prevention & control; Protein transport; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; ran GTP-Binding Protein - genetics; ran GTP-Binding Protein - metabolism; Senescence; Young Adult
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.aar5401

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 -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.