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Vol. 17, Issue 6, 2646-2660, June 2006

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NuSAP, a Mitotic RanGTP Target That Stabilizes and Cross-links Microtubules

Katharina Ribbeck^*, Aaron C. Groen^,, Rachel Santarella^*,, Markus T. Bohnsack^,, Tim Raemaekers^,||, Thomas Köcher^¶, Marc Gentzel^*, Dirk Görlich, Matthias Wilm^*, Geert Carmeliet^#, Timothy J. Mitchison, Jan Ellenberg^*, Andreas Hoenger^@, and Iain W. Mattaj^*

*European Molecular Biology Laboratory, D-69117 Heidelberg, Germany; Department of Systems Biology, Harvard Medical School, Boston, MA 02115; Zentrum für Molekulare Biologie Heidelberg, D-69120 Heidelberg, Germany; ^||Membrane Trafficking Laboratory, Center for Human Genetics/VIB04, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; ^¶Uppsala Biomedical Centrum, SE-75 123 Uppsala, Sweden; ^#Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Gasthuisberg, B-3000 Leuven, Belgium; and ^@The Boulder Laboratory for 3-D Electron Microscopy of Cells, University of Colorado, Boulder, CO 80309

Submitted December 28, 2005; Revised March 13, 2006; Accepted March 14, 2006
Monitoring Editor: Karsten Weis

Nucleolar and spindle-associated protein (NuSAP) was recently identified as a microtubule- and chromatin-binding protein in vertebrates that is nuclear during interphase. Small interfering RNA-mediated depletion of NuSAP resulted in aberrant spindle formation, missegregation of chromosomes, and ultimately blocked cell proliferation. We show here that NuSAP is enriched on chromatin-proximal microtubules at meiotic spindles in Xenopus oocytes. When added at higher than physiological levels to Xenopus egg extract, NuSAP induces extensive bundling of spindle microtubules and causes bundled microtubules within spindle-like structures to become longer. In vitro reconstitution experiments reveal two direct effects of NuSAP on microtubules: first, it can efficiently stabilize microtubules against depolymerization, and second, it can cross-link large numbers of microtubules into aster-like structures, thick fibers, and networks. With defined components we show that the activity of NuSAP is differentially regulated by Importin (Imp) , Imp, and Imp7. While Imp and Imp7 appear to block the microtubule-stabilizing activity of NuSAP, Imp specifically suppresses aspects of the cross-linking activity of NuSAP. We propose that to achieve full NuSAP functionality at the spindle, all three importins must be dissociated by RanGTP. Once activated, NuSAP may aid to maintain spindle integrity by stabilizing and cross-linking microtubules around chromatin.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-12-1178) on March 29, 2006.

These authors contributed equally to this work.

Address correspondence to: Katharina Ribbeck ( ribbeck{at}embl.de)

Abbreviations used: importin, Imp; TR, transport receptors.

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