At the Meeting: Holding the Gates of the Nuclear ‘Fortress’

Newswise — Old textbooks present the cell nucleus as a 'bag of chromosomes' floating in cytoplasm. However the "new" nucleus emerging from current research is a dynamic organelle and a powerful fortress that protects the genome while exercising critical control over cell fate and gene activity.

The gateway to the genome is the nuclear pore complex (NPC), a cellular megalith 30 times the size of a ribosome. Each NPC assembles from a library of soluble proteins plus two membrane proteins into an elaborate structure that spans both membranes of the nuclear envelope. The nucleus has many NPCs, which examine all traffic in and out of the nucleus, and only allow the transport of molecules bearing the proper import or export "licenses" . Viruses such as HIV-1 and polio have evolved crafty ways to clothe or unclothe themselves to sneak through NPCs. Several genetic disorders have been linked to mistakes in nuclear trafficking. To better understand what holds the NPC together, Amnon Harel, Douglass Forbes, Michael Elbaum and colleagues at the University of California, San Diego, and the Weizmann Institute in Israel decided to knock the NPC apart. In new work presented at the American Society for Cell Biology's 43rd Annual Meeting in San Francisco, the researchers report that one subunit, the newly discovered Nup107-160 complex, is the linchpin. Remove it and the gateway doesn't merely collapse, it disappears completely, leaving the fortress sealed and inaccessible.

Harel and colleagues were able to eliminate the Nup107-160 complex from nuclei grown in cell-free extracts made from frog eggs. The resulting nuclei were tiny and severely defective for nuclear import and DNA replication. On closer inspection, the change was even more startling: the nuclei had nuclear membranes but were completely devoid of NPCs. The researchers concluded that the Nup107-160 complex acts as a linchpin for nuclear pore assembly—a subunit so critical that its absence destroys all obvious nuclear pore organization.

In a separate approach, Harel and colleagues also identified a surprising new inhibitor of nuclear assembly, importin-beta. This abundant protein inhibits two distinct stages of nuclear assembly: vesicle-vesicle fusion to form the inner and outer nuclear membranes, and subsequent assembly of NPCs, pointing to a possible connection between importin-beta and the Nup 107-160 complex. This finding adds to growing evidence that importin-beta is a master regulator of access to the genomic fortress.

Linchpins and Inhibitors: Regulated Assembly of the Nuclear Pore Complex, A. Harel,1 A. V. Orjalo,1 R. Chan,1 A. Lachish-Zalait,2 E. Zimmerman,2 T. Vincent,1 S. Vasu,1 S. Shah,1 M. Elbaum,2 D. J. Forbes1 ; 1 Section of Cell and Developmental Biology, Division of Biology, University of California, San Diego, La Jolla, CA, 2 Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel