During early animal embryogenesis rapid cell cycles in the absence of substantial cell growth result in the progressive reduction of cell size. Although it has been observed that nuclear and mitotic spindle size decrease when cell volume is reduced, how intracellular scaling occurs remains elusive. Brownlee and Heald now suggest that the partitioning of importin-α at the plasma membrane, driven by palmitoylation, contributes to intracellular scaling.

Credit: V. Summersby/Springer Nature Limited

Importin-α is a nucleocytoplasmic transport factor that has been shown to associate with the plasma membrane and become less abundant in the cytoplasm of cells in Xenopus laevis embryos during early development. The authors found that this plasma membrane association is driven by importin-α palmitoylation. Moreover, the calculated increase in cell surface-to-volume ratio associated with early X. laevis development is consistent with a dynamic redistribution of importin-α from the cytoplasm to the membrane with decreasing cell size. This indicates that palmitoylated importin-α can respond to changes in cell size and relocate to the plasma membrane as cell size decreases.

In X. laevis egg extracts, pharmacological blockade of palmitoylation increased spindle length and nuclear size. The opposite effect was observed when de-palmitoylation was inhibited, suggesting that palmitoylation and membrane association of importin-α support nuclear and spindle size reduction. This was confirmed in physiologically relevant conditions — in microfluidic cell-like droplets of varying sizes, in X. laevis embryos and in cultured human cells.

palmitoylated importin-α can respond to changes in cell size and relocate to the plasma membrane

Increased palmitoylation was associated with reduced interaction of importin-α with its cargoes (nuclear localization signal (NLS)-containing proteins), including kinesin Kif2a, which depolymerizes spindle microtubules, and the nuclear lamina component lamin B3, which is a limiting factor for nuclear growth. Thus, palmitoylation and membrane localization of importin-α drive nuclear and spindle downscaling by impeding the interaction of importin-α with its cargoes, thereby modulating their cellular distribution and function. How importin-α palmitoylation is regulated and how this modification and membrane partitioning affect other NLS-containing cargoes of importin-α remain to be investigated.