A mutant protein responsible for Hutchinson-Gilford Progeria syndrome (HGPS) bars large proteins from entering the nucleus, Snow et al. reveal.

The culprit in HGPS, a fatal disease that resembles premature aging, is Progerin. This defective version of the lamin A protein impairs cells in many ways, including reducing nuclear levels of the RanGTPase. Ran is crucial for nuclear import and export, as it stimulates unloading of cargo that has just entered the nucleus and loading of cargo that’s ready to exit. Progerin also impedes the import of Tpr, which forms the basket-like structure on the inner side of nuclear pores. But the mechanism behind this exclusion wasn’t clear.

One possibility is that Progerin disrupts the activity of Tpr’s nuclear localization sequence (NLS). To test this idea, Snow et al. replaced Tpr’s NLS with the localization sequence from the SV40 virus T antigen, a protein that readily enters the nucleus. The modified Tpr was still locked out, however, suggesting that the effect wasn’t related to its NLS.

Tpr forms a dimer that weighs in at 535 kD, making it one of the largest proteins to traverse nuclear pores. Snow et al. found that Progerin limits the nuclear import of three other hefty proteins—Tip60, p400, and Orc2. This size effect stems from the reduction in nuclear Ran levels triggered by Progerin. For reasons that are still unclear, large cargoes require more Ran to enter the nucleus. These findings suggest that some cellular defects of HGPS might result from the exclusion of large cargoes, such as multisubunit enzyme complexes, from the nucleus.

et al
J. Cell Biol.

Author notes

Text by Mitch Leslie