Pioneering Research

R e s e a r ch highlights

Nature Reviews Molecular Cell Biology | AOP, published online 9 May 2008; doi:10.1038/nrm2416

DOI: 10.1038/nrm2416 gene e x pression Pioneering research

The pioneer round of protein also showed that rapamycin inhibits co-immunoprecipitates with decay translation represents the first pas- the phosphorylation of substrates factors, which suggests that these sage of ribosomes on newly spliced in the CBP-bound mRNA–protein interactions occur after nonsense mRNAs that are associated with complexes (or mRNPs), suggesting a codon recognition. The authors the cap-binding protein (CBP) role for mTOR signalling in pioneer demonstrated that phosphorylated heterodimer CBP80/20. During this translation initiation. In addition, UPF1 also interacts with eukaryotic round, nonsense-mediated mRNA the activated form of the mTOR initiation factor (eIF)3 and inhibits decay (NMD) occurs following effector S6 protein kinase-1 (S6K1) eIF3-dependent translation by nonsense codon recognition. This was present in these complexes. The preventing the eIF3-mediated con- Met mRNA surveillance pathway requires authors identified an S6K1-specific version of 40S–Met-tRNAi –mRNA the exon-junction complex (EJC), interactor named SKAR, which asso- to translationally competent Met which also influences the translation ciates with CBP80-bound mRNPs 80S–Met-tRNAi –mRNA initiation efficiency of spliced mRNAs. Two in a splicing-dependent manner and complexes. However, it is not clear studies now provide unexpected binds to the EJC. So, mTOR and how the binding of phosphorylated insights into how pre-mRNA S6K1 contribute to the assembly of UPF1 to eIF3 inhibits its function. splicing, mRNA surveillance and an efficient pioneer-round initiation Consistent with the notion that translation are connected. complex. phosphorylated UPF1 mediates By investigating a possible link Does SKAR recruit S6K1 to translational repression during NMD between mammalian target of newly spliced mRNA? And does the through eIF3, nonsense-containing rapamycin (mTOR) signalling, which recruitment of S6K1 affect the splic- mRNA that initiates translation positively regulates protein synthesis, ing-dependent translation efficiency? using an eIF3-dependent mechanism and splicing-modulated protein trans- Knocking down the expression was immune to NMD. On the basis lation, Ma et al. found that rapamycin of SKAR or the EJC component of their observations, the authors inhibits the increase in translation eIF4AIII led to a decrease of S6K1 suggest that “translational repres- efficiency gained by splicing. They that is associated with CBP80-bound sion is a key transition that precedes mRNP, and a reduction in the phos- mRNA delivery to the degradation phorylation of mRNP-associated machinery.” proteins. In addition, the knockdown So, the pioneer round of trans of S6K1, SKAR and eIF4AIII led to lation provides an intriguing example a similar decrease in the translation of how various gene-regulatory pro efficiency of spliced mRNAs. So, an cesses, such as pre-mRNA splicing, intact EJC and SKAR are essential mRNA degradation and translational for the recruitment of S6K1, which efficiency, are functionally linked modulates the splicing-dependent through highly intricate regulatory increase in translational efficiency. complexes and events. How the EJC contributes to transla- Arianne Heinrichs

tion of newly synthesized mRNAs ORIGINAL RESEARCH PAPERS Ma, X. M. et al. and how the pioneer round contrib- SKAR links pre-mRNA splicing to mTOR/S6K1- utes to overall translational efficiency mediated enhanced translation efficiency of are issues that remain to be addressed. spliced mRNAs. Cell 133, 303–313 (2008) | The EJC also participates in NMD, Isken, O. et al. Upf1 phosphorylation triggers which is triggered when translation translational repression during nonsense- terminates sufficiently upstream mediated mRNA decay. Cell 133, 314–327 (2008) of an EJC, and the consequential Further Reading Amrani, N. et al. binding of UPF1 to the EJC results in Early nonsense: mRNA decay solves a translational problem. Nature Rev. Mol. Cell Biol. UPF1 phosphorylation. Isken et al. 7, 415–425 (2006) showed that phosphorylated UPF1