SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs (Cell, 2008, 133:303-313)

報告日期: 2008/12/23
報告時間: 16:00/16:50
報告學生: 石聿恒
講評老師: 曾大千
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971223-2.pdf

SKAR Links Pre-mRNA Splicing to mTOR/S6K1-mediated Enhanced Translation Efficiency of Spliced mRNAs

Xiaoju Max Ma, Sang-Oh Yoon, Celeste J. Richardson, Kristina Jülich, and John Blenis

Cell 2008 133:303-313

 

Speaker: Yu-Heng Shih  

Commentator: Dr. Ta-Chien Tseng 

Date/Time: 2008/12/23, 16:00~16:50

Place: Room 602, College of medicine

 

Abstract

In most eukaryotes, various protein complexes recruit to newly synthesis pre-mRNAs to facilitate mRNA metabolism, including splicing, mRNA surveillance, exporting, and translation. Recently studies showed these RNA processing mechanism were found to connect to each other, Such as the cap-binding protein heterodimer CBP80/20 can interact with exon junction complex (EJC) and that are required for a series steps of mRNA metabolism, and they are thought to be linked to facilitate protein synthesis. It suggests that the efficient splicing may have evolved to enhance translation initiation through these components of CBP80/20 and EJC. Several studies also showed that translational initiation steps are regulated by mammalian target-of-rapamycin complex (mTOR) and ribosomal subunit protein S6 kinase 1 (S6K1) signaling. However, the detail molecular mechanisms by which the EJC enhances translation are poorly understood. In this paper, the authors first found that the mTOR/S6K1 signaling, which associated to CBP80-bound protein complex, is regulated under splicing-modulated protein synthesis. The authors wondered whether the EJC is somehow linking between this signaling. In immunoprecipitation and in vitro splicing experiment, they demonstrated that an S6K1 specific ineteractor SKAR (S6K1 Aly/REF-like substrate), one component of the EJC, recruit S6K1 to newly spliced mRNA. Known down of SKAR or the core EJC component, eIF4AIII, results in a decrease of activated S6K1 associated with CBP80 and a reduction in the translation efficiency of spliced mRNA. The same result occurred in S6K1 knockdown experiment. Consequently, S6K1, the EJC, and SKAR are positive factors that modulate the translational yield of introns-containing and spliced mRNA. Through SKAR the EJC serves to facilitate the association of S6K1 with CBP80-bound mRNPs and to mediate following phosphorylation events, potentially contributing to efficient translation. Together these results, the authors give insight into the molecular mechanism underlying a splicing-dependent increase in translational efficiency and provide a new model for realizing protein synthesis modulated by mTOR signaling.

 

References

1.     Ishugaki Y., et al., 2001, Evidence for a Pioneer Round of mRNA Translation: mRNA Subject to Nonsense-Mediated Decay in Mammalian Cells Are Bound by CBP80 and CBP20. Cell, 106: 607

2.     Holz M.K., et al., 2005, mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events. Cell, 123:569