Cells with too much RCC1 (bottom two cells) are impaired in nuclear import.

Nuclear import is slowed by too much of a good thing. So says a new systems model of nuclear import from Riddick and Macara (page 1027), which predicts that high levels of the cargo carrier Importin-β or the RanGEF RCC1 inhibit import.

With its simple nucleus-versus-cytoplasm architecture, import is a good candidate for systems analysis. Most of the components have been identified, and biochemical experiments have already determined many of the relevant rate constants. Previous models outlined how Ran transport affected steady-state cargo distribution.Now, Riddick and Macara look at the kinetics of cargo import. Their model does what any good model should: it makes unexpected predictions that can be tested experimentally, and it reveals weaknesses in the current understanding of the system.

Surprises came in the form of predictions that more Importin-β or RanGTP-producing RCC1 would inhibit transport. As RanGTP gradients across the pore drive import, the authors expected more nuclear RCC1 would be better. But the model said that excess RCC1 would bind to and sequester nuclear Ran. Likewise, the model predicted that nuclear Ran would be depleted by extra Importin-β, because the excess carrier would enter the nucleus even without associated cargo before leaving with its normal dose of RanGTP.

Using in vivo import assays, the authors show that the predictions are valid—import was inhibited by RCC1 or Importin-β levels above physiological concentrations. Cells thus have just enough, but not too much, of these factors.

Other predictions that held true in vivo were less surprising. For instance, substrate import rates were limited by the concentration of Ran and Importin-α, which links many cargos to Importin-β.

One prediction was proven wrong. The model suggested that RanBP1, which promotes the hydrolysis of RanGTP in the cytoplasm, is not limiting for import. In vivo, however, extra RanBP1 improved import kinetics. This discord indicates that RanBP1 probably has functions that are not yet understood. Future studies can now focus on identifying these functions.