Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway
Larrieu D, Viré E, Robson S, Breusegem SY, Kouzarides T, Jackson SP.
Science Signaling 11, eaar5401
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.