Conserved mRNA-granule component Scd6 targets Dhh1 to repress translation initiation and activates Dcp2-mediated mRNA decay in vivo

Quira Zeidan, Feng He, Fan Zhang, Hongen Zhang, Allan Jacobson and Alan G Hinnebusch

PLOS Genetics, 2018, vol. 14, issue 12, 1-42

Abstract: Scd6 protein family members are evolutionarily conserved components of translationally silent mRNA granules. Yeast Scd6 interacts with Dcp2 and Dhh1, respectively a subunit and a regulator of the mRNA decapping enzyme, and also associates with translation initiation factor eIF4G to inhibit translation in cell extracts. However, the role of Scd6 in mRNA turnover and translational repression in vivo is unclear. We demonstrate that tethering Scd6 to a GFP reporter mRNA reduces mRNA abundance via Dcp2 and suppresses reporter mRNA translation via Dhh1. Thus, in a dcp2Δ mutant, tethered Scd6 reduces GFP protein expression with little effect on mRNA abundance, whereas tethered Scd6 has no impact on GFP protein or mRNA expression in a dcp2Δ dhh1Δ double mutant. The conserved LSm domain of Scd6 is required for translational repression and mRNA turnover by tethered Scd6. Both functions are enhanced in a ccr4Δ mutant, suggesting that the deadenylase function of Ccr4-Not complex interferes with a more efficient repression pathway enlisted by Scd6. Ribosome profiling and RNA-Seq analysis of scd6Δ and dhh1Δ mutants suggests that Scd6 cooperates with Dhh1 in translational repression and turnover of particular native mRNAs, with both processes dependent on Dcp2. Our results suggest that Scd6 can (i) recruit Dhh1 to confer translational repression and (ii) activate mRNA decapping by Dcp2 with attendant degradation of specific mRNAs in vivo, in a manner dependent on the Scd6 LSm domain and modulated by Ccr4.Author summary: Previous work showed that Scd6 homologs in Drosophila, Xenopus, and humans are associated with translationally repressed mRNAs in RNA granules, and that they interact with other mRNA silencing factors, including homologs of RNA helicase Dhh1. However, there is little evidence that such Scd6 homologs are critical for translational repression or degradation of specific mRNAs in vivo. Yeast Scd6 interacts with the mRNA decapping enzyme and was shown to inhibit translation in cell extracts through binding to cap-binding translation initiation factor eIF4G. However, it was unknown whether Scd6 represses translation or accelerates degradation of any specific mRNAs in vivo, or whether Scd6 requires the decapping enzyme or its activators for such events. Here we show that tethering Scd6 stimulates the degradation or translational repression of reporter mRNAs in yeast, collaborating with Dhh1 for translational repression and the decapping enzyme Dcp2/Dcp1 for mRNA turnover. Using ribosome profiling we further identify groups of native mRNAs that appear to be targeted for degradation or translational repression by Scd6 and Dhh1 and find unexpectedly that Dcp2 is necessary for translational repression as well as enhanced degradation of most such mRNAs. Thus, Scd6 partners with Dhh1 and Dcp2 to mediate translational repression and degradation of specific mRNAs in vivo.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1007806

DOI: 10.1371/journal.pgen.1007806

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