Article abstract
Nature Structural & Molecular Biology 15, 444 - 451 (2008)
Published online: 20 April 2008 | doi:10.1038/nsmb.1401
A role for ubiquitin in the spliceosome assembly pathway
Priya Bellare1, Eliza C Small2, Xinhua Huang3, James A Wohlschlegel3, Jonathan P Staley4 & Erik J Sontheimer1
Abstract
The spliceosome uses numerous strategies to regulate its function in mRNA maturation. Ubiquitin regulates many cellular processes, but its potential roles during splicing are unknown. We have developed a new strategy that reveals a direct role for ubiquitin in the dynamics of splicing complexes. A ubiquitin mutant (I44A) that can enter the conjugation pathway but is compromised in downstream functions diminishes splicing activity by reducing the levels of the U4/U6-U5 small nuclear ribonucleoprotein (snRNP). Similarly, an inhibitor of ubiquitin's protein-protein interactions, ubistatin A, reduces U4/U6-U5 triple snRNP levels in vitro. When ubiquitin interactions are blocked, ATP-dependent disassembly of purified U4/U6-U5 particles is accelerated, indicating a direct role for ubiquitin in repressing U4/U6 unwinding. Finally, we show that the conserved splicing factor Prp8 is ubiquitinated within purified triple snRNPs. These results reveal a previously unknown ubiquitin-dependent mechanism for controlling the pre-mRNA splicing pathway.
- Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208, USA.
- Department of Biochemistry and Molecular Biology, University of Chicago, 920 East 58th Street, Chicago, Illinois 60637, USA.
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive South, Los Angeles, California 90095-1737, USA.
- Department of Molecular Genetics and Cell Biology, University of Chicago, 920 East 58th Street, Chicago, Illinois 60637, USA.
Correspondence to: Erik J Sontheimer1 e-mail: erik@northwestern.edu
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