Safeguarding the cell nucleus
News
The nucleus is guarded by a highly secure door, the so-called nuclear pore, thatcontrols the transport of substances from the cytoplasm to the cell nucleus and back. Aresearch group at the University of Basel has now shown that different shuttle proteinsoccupy the nuclear pore to prevent unsolicited leakage of molecules. These proteinsform an escape-proof, failsafe mechanism by compensating for one another to fortifythe pore.
The nuclear pore is responsible for regulating the transport of proteins from the cytoplasminto the cell nucleus and for ushering RNA out of it. It works like a molecular sieve thatcontrols the entry and exit of cargo-carrying shuttle proteins. The molecular sieve interactswith shuttle proteins, which, like gatekeepers, decide which proteins are allowed to enterand which are not.
Argovia-Professor Roderick Lim from the Biozentrum of the University ofBasel aims to resolve this enigmatic selective transport system. Histeam, in collaboration with the Swiss Nanoscience Institute, hasnow examined three prominent shuttle proteins in human cells anduncovered that their crowding at nuclear pores is important forpreventing unwanted leakage into and out of the nucleus.
The number of shuttle proteins that occupy the pore depends ontheir concentrations within the cell. However, when one shuttleprotein is reduced, another shuttle protein can take its place toreinforce the pore. The results of this novel compensation mechanism have now beenpublished in the Journal of Cell Biology.
Interchangeable shuttle proteins safeguard the nuclear pore
“It turns out that the shuttle proteins, although they are from the same receptor family, differin function in terms of the cargo they carry, localization and concentration,” says Dr. JoannaKalita, first author of the study. The shuttle proteins, which act like gatekeepers at the nuclearpore and decide which cargoes are allowed to enter the cell nucleus and which have to beescorted out, reside in the nuclear pore at varying amounts – depending on their respectiveconcentrations.
When the researchers changed the concentration of one of theshuttle proteins, the number of the other two proteins thatoccupied the nuclear pore also changed. “If the total number ofshuttle proteins in the pore gets reduced, the nuclear porebecomes leaky. Thus, cells rely on a mechanism that allows theloss of one shuttle protein to be compensated by the increase ofanother. That’s how the shuttle proteins safeguard the nuclearpores,” says Kalita.
Diseases caused by defective nuclear pores
Damage to this biological security system is detrimental to cells, and has been associatedwith cancer and neurodegenerative diseases. Viruses that infect cells, such as SARS-CoV-2,can also trap these shuttle proteins away from the nuclear pore to impair its functionality.”This can lead to defects in the nuclear pore and as a consequence, undesirable substancescan freely penetrate the nuclear pores and ‘poison’ the nucleus.
Conversely, substances important for the cell nucleus are no longer imported. Clearly, deeperinsights into nuclear pore function will be important for understanding the causes andconsequences of defective nuclear transport with respect to disease,” explains Lim.
Original publication
Joanna Kalita, Larisa E. Kapinos, Tiantian Zheng, Chantal Rencurel, Anton Zilman undRoderick Y. H. Lim
Karyopherin enrichment and compensation fortifies the nuclear pore complex againstnucleocytoplasmic leakage.
Journal of Cell Biology (2022), doi: 10.1083/jcb.20210810