SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome

Julian P. Venables, Caroline Dalgliesh, Maria Paolo Paronetto, Lindi Skitt, Jared K. Thornton, Philippa T. Saunders, Claudio Sette, Keith T. Jones, David J. Elliott

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1525-1534
Number of pages10
JournalHuman Molecular Genetics
Volume13
Issue number14
DOIs
Publication statusPublished - Jul 15 2004

ASJC Scopus subject areas

  • Genetics

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    Venables, J. P., Dalgliesh, C., Paronetto, M. P., Skitt, L., Thornton, J. K., Saunders, P. T., Sette, C., Jones, K. T., & Elliott, D. J. (2004). SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome. Human Molecular Genetics, 13(14), 1525-1534. https://doi.org/10.1093/hmg/ddh165