Nuclear Pore Complex Acetylation Regulates mRNA Export and Cell Cycle Commitment in Budding Yeast

Abstract

Nuclear pore complexes (NPCs) mediate communication between the nucleus and the cytoplasm and regulate gene expression by interacting with transcription and mRNA export factors. We find that Esa1, the catalytic subunit of the yeast lysine acetyl-transferase NuA4 complex, acetylates the nuclear basket component Nup60 to promote mRNA export. Acetylation of Nup60 recruits mRNA export factors to the nuclear basket, including the scaffolding subunit of the Transcription and Export 2 (TREX-2) complex, Sac3. Esa1-dependent nuclear export of mRNAs promotes entry into S phase, and is inhibited by the Hos3 deacetylase in G1 daughter cells to restrain their premature commitment to a new cell division cycle. This mechanism also inhibits expression of the nutrient-regulated GAL1 gene specifically in daughter cells. These results reveal how acetylation contributes to the functional plasticity of NPCs in specific cell types, and demonstrate how the evolutionarily conserved NuA4 complex regulates gene expression dually at the level of mRNA synthesis and export by modifying the nucleoplasmic entrance to nuclear pores.

The Nuclear Pore Complex: Birth, Life, and Death of a Cellular Behemoth

“…Such effects have been reported for mRNA and protein export [211][212][213][214][215]. For example, the budding yeast mRNA export factor Sac3 is released from the nuclear basket in newly budded daughter cells, which leads to an inhibition of mRNA export [214], and similarly, bulk mRNA export is inhibited by the release of the cytoplasmic mRNA export factor Dbp5 from the NPC during glucose starvation [212]. Interestingly, the availability of transport cargo may also influence NPC composition, as interference with mRNA transcription or 3 end processing perturbs the association of the budding yeast nuclear basket NUP Mlp1 with the NPC [200].…”

“…First, modulation of the NTR complement at the NPC can regulate the available transport pathways. Such effects have been reported for mRNA and protein export [211][212][213][214][215]. For example, the budding yeast mRNA export factor Sac3 is released from the nuclear basket in newly budded daughter cells, which leads to an inhibition of mRNA export [214], and similarly, bulk mRNA export is inhibited by the release of the cytoplasmic mRNA export factor Dbp5 from the NPC during glucose starvation [212].…”

“…Peripheral and membrane NUPs in particular exhibit significant variability in expression levels across different cell types [65,[207][208][209]. However, more acute modifications of NPCs, e.g., during stress response signaling [210][211][212][213], differentiation [211] or in relation to the cell cycle [202,214,215], require regulatory mechanisms that can act on shorter time scales and are potentially restricted to subsets of NPCs. Two such mechanisms have been described in the generation of NPC variants: PTMs and proteolytic cleavage.…”

“…Certain stress conditions also result in the phosphorylation, ubiquitination, and SUMOylation of NUPs, in particular those in the nuclear basket [216][217][218], and these modifications can regulate the interaction between NUPs [217,219]. Furthermore, acetylation of the nuclear basket NUP Nup60 was recently implicated in the generation of modified NPCs in budding yeast [205,214,215]. These PTMs are likely only a small fraction of regulatory modifications involved in regulating NPC function, and more work is needed to identify and characterize PTMs on NUPs.…”