Nuclear import pathway key to rescuing dominant progerin phenotypes

Abstract

In this issue of Science Signaling, Larrieu et al show that an acetyltransferase inhibitor that rescues many dominant nuclear phenotypes caused by progerin, a truncated form of lamin A, does so by releasing the specialized nuclear import receptor TNPO1 from sequestration by microtubules. This release enables TNPO1-dependent import of specific cargoes, including the nuclear pore protein Nup153 and the heterogeneous nuclear ribonucleoprotein hnRNPA1, thus restoring the functionality of nuclear pore complexes, rebalancing the nucleocytoplasmic Ran gradient, and normalizing gene expression.

Fig. 1.. Proposed mechanism by which Remodelin rescues NPC structure, nuclear import, and downstream functions in HGPS cells.

In normal cells, NPC assembly during interphase requires TNPO1-dependent import of the nucleoporin Nup153. Most Ran in the cytoplasm is bound to RanGDP, whereas most Ran in the nucleus is bound to RanGTP. RanGTP is critical for nuclear import because it binds to importins to stimulate the release of cargo proteins such as Nup153 (1). Nup153 forms the NPC basket, binds to lamin A, recruits Tpr to the basket (2), and anchors Tpr oligomers that extend into the nucleoplasm (3). These extended networks are necessary for Nup153 and other mobile nucleoporins to associate with transcriptionally active chromatin in the nuclear interior (4). Transcriptionally silent chromatin associates with lamins near the inner membrane of the nuclear envelope. TNPO1 is also required to import the mRNA-splicing protein hnRNPA1, which is released in the nucleus upon RanGTP binding to TNPO1. The acetyltransferase NAT10 covalently attaches acetyl groups (Ac) to many target proteins, including microtubules (MT). In cells from HGPS patients, progerin accumulates at the inner membrane of the nuclear envelope and disrupts normal nuclear lamina organization; other phenotypes include reduced accumulation of nuclear RanGTP, loss of heterochromatin positioning near the nuclear envelope, transcriptional dysregulation, and premature cellular senescence. Because NAT10 activity and microtubule stability are increased in HGPS cells, NAT10-mediated hyperacetylation of tubulin is proposed to explain the increased association of TNPO1 with microtubules in HGPS cells. Sequestration of TNPO1 by microtubules reduces TNPO1-dependent import of cargoes, such as Nup153 and hnRNPA1, leading to defective NPC assembly and transcriptional dysregulation. Treating HGPS cells with Remodelin, which inhibits NAT10 activity, releases TNPO1 from microtubules, thereby restoring TNPO1-dependent import of Nup153, hnRNPA1, and other cargoes. This, in turn, restores NPCs, rebalances the nucleocytoplasmic Ran gradient, and normalizes gene expression.