Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway.
American Association for the Advancement of Science
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Larrieu, D., Viré, E., Robson, S., Breusegem, S., Kouzarides, T., & Jackson, S. (2018). Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway.. Science signaling, 11 (537)https://doi.org/10.1126/scisignal.aar5401
Hutchinson-Gilford progeria syndrome (HGPS) is an incurable premature ageing disease. Identifying deregulated biological processes in HGPS might thus help define novel therapeutic strategies. Fibroblasts from HGPS patients display defects in nucleo-cytoplasmic shuttling of the GTP-bound form of the small GTPase Ran (RanGTP), which leads to abnormal transport of proteins into the nucleus. Here, we report that microtubule stabilisation in HGPS cells sequestered the non-classic nuclear import protein Transportin-1 (TNPO1) in the cytoplasm, thus affecting the nuclear localisation of its cargos, including the nuclear pore protein NUP153. Consequently, nuclear Ran, nuclear anchorage of the nucleoporin TPR, and chromatin organisation 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 localisation, 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 ageing and underscores the potential for NAT10 inhibition as a possible therapeutic strategy for HGPS, and perhaps also for pathologies associated with normal ageing.
Cells, Cultured, Cell Nucleus, Microtubules, Fibroblasts, Humans, Progeria, ran GTP-Binding Protein, beta Karyopherins, Nuclear Pore Complex Proteins, Proto-Oncogene Proteins, Case-Control Studies, Active Transport, Cell Nucleus, Phenotype, Adult, Aged, 80 and over, Child, Female, Male, Young Adult, N-Terminal Acetyltransferase E, Cellular Senescence
Cancer Research UK (18796)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (11224)
Wellcome Trust (206242/Z/17/Z)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Cancer Research UK (A14492)
External DOI: https://doi.org/10.1126/scisignal.aar5401
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280474