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MBC in Press, published online ahead of print August 7, 2003
Mol. Biol. Cell 10.1091/mbc.E03-05-0275

A more recent version of this article appeared on November 1, 2003
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Submitted on May 2, 2003
Revised on July 11, 2003
Accepted on July 14, 2003

Importin Beta Negatively Regulates Nuclear Membrane Fusion and NPC Assembly

Amnon Harel1, Rene C. Chan1, Aurelie Lachish-Zalait2, Ella Zimmerman2, Michael Elbaum2, and Douglass J. Forbes1*

1 Section of Cell and Developmental Biology, Division of Biological Sciences 0347, Room 2124A Pacific Hall, University of California - San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0347
2 Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot 76100, Israel

* Corresponding author. E-mail address: dforbes{at}ucsd.edu.

Assembly of a eukaryotic nucleus involves three distinct events: membrane recruitment, fusion to form a double nuclear membrane, and nuclear pore complex (NPC) assembly. Here we report that importin {beta} negatively regulates two of these events, membrane fusion and NPC assembly. When excess importin {beta} is added to a full Xenopus nuclear reconstitution reaction, vesicles are recruited to chromatin but their fusion is blocked. The importin {beta} down-regulation of membrane fusion is Ran-GTP reversible. Indeed, excess RanGTP (RanQ69L) alone stimulates excessive membrane fusion, leading to intranuclear membrane tubules and cytoplasmic annulate lamellae-like structures. We propose that a precise balance of importin {beta} to Ran is required to create a correct double nuclear membrane and simultaneously to repress undesirable fusion events. Interestingly, truncated importin {beta} 45-462 allows membrane fusion, but produces nuclei lacking any NPCs. This reveals distinct importin {beta}-regulation of NPC assembly. Excess full-length importin {beta} and {beta} 45-462 act similarly when added to prefused nuclear intermediates, i.e., both block NPC assembly. The importin {beta} NPC block, which maps downstream of GTP{gamma}S- and BAPTA-sensitive steps in NPC assembly, is reversible by cytosol. Remarkably, it is not reversible by 25 µM RanGTP, a concentration that easily reverses fusion inhibition. This report, using a full reconstitution system and natural chromatin substrates, significantly expands the repertoire of importin {beta}. Its roles now encompass negative regulation of two of the major events of nuclear assembly: membrane fusion and NPC assembly.




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