Human Molecular Genetics Advance Access originally published online on May 26, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 14 1525-1534
DOI: 10.1093/hmg/ddh165
Human Molecular Genetics, Vol. 13, No. 14 © Oxford University Press 2004; all rights reserved
SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome
1Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK, 2Cell and Developmental Physiology Research Group, School of Cell and Molecular Biosciences, The Medical School, Framlington Place, University of Newcastle, Newcastle NE2 4HH, UK, 3Department of Public Health and Cell Biology, Section of Anatomy, University of Rome ‘Tor Vergata’, Rome, Italy and 4MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, 49 Little France Crescent, Edinburgh EH16 4SB, UK
Received April 22, 2004; Accepted May 12, 2004
T-STAR is one of three members of the SAM68 family of RNA-binding proteins that have been shown to be involved in various gene expression pathways including the control of pre-mRNA splicing. We employed a two-hybrid screen to identify proteins that interact with human T-STAR. The predominant interacting proteins were the E3 ubiquitin ligases SIAH1 and SIAH2. We found that SIAH1 bound to an octapeptide sequence in T-STAR targeting it for proteasome-dependent degradation. Rodent T-STAR orthologues (also known as etoile or SLM2) were not targeted for degradation by SIAH1. However a double amino acid substitution of mouse T-STAR that mimics the human SIAH1-binding site brought mouse T-STAR under in vivo control of SIAH1. Using a minigene transfection assay for alternative splicing activity we showed that human T-STAR, like its rodent orthologues can influence splice site choice and that human, but not mouse, T-STAR-dependent alternative splicing is modulated by SIAH1. Western blots of protein from purified germ cells indicated that SIAH1 protein expression peaks in meiosis. In mouse, T-STAR is co-expressed with SIAH1 during meiosis but, in humans, T-STAR is only strongly expressed after meiosis. Comparative sequence analysis showed SIAH-mediated proteasomal degradation of T-STAR has evolved in the primate lineage. Collectively these data suggest that SIAH-mediated down regulation of alternative splicing may be an important developmental difference between otherwise highly conserved T-STAR proteins.
* To whom correspondence should be addressed. Tel: +44 1912418694; Fax: +44 1912418666; Email: david.elliott{at}ncl.ac.uk
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