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EIF4A2 drives repression of translation at initiation by Ccr4-Not through purine rich motifs in th 5'UTR

ABSTRACT: Here we show eIF4A2 is a major effector of the represive miRNA pathway functioning via the Ccr4_Not complex; through its interaction with the Ccr4-Not complex eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar properties to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5'UTR directly upstream of the AUG codon.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Rebekah Jukes-Jones

LAB HEAD: Ania Wilczynska

PROVIDER: PXD015772 | Pride | 2019-10-10

REPOSITORIES: Pride

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			Action	DRS
	HEDDA_280313001.mzid.gz	Mzid
	HEDDA_280313001.mzid_HEDDA_280313001.MGF	Mzid
	HEDDA_280313001.mzid_HEDDA_280313001.pride.mgf.gz	Mzid
	HEDDA_280313001.raw.zip	Raw
	HEDDA_280313002.mzid.gz	Mzid

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eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR.

Project description:Regulation of the mRNA life-cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Here we show eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar properties to chemically inhibited eIF4A1. We demonstrate that eIF4A2 exerts it repressive effect by binding purine-rich motifs which are enriched in the 5’UTR directly upstream of the AUG start codon. The data supports a model whereby purine motifs towards the 3’ end of the 5’UTR are associated with increased ribosome occupancy and possible uORF activation similar to that observed for mRNAs affected by inhibited eIF4A1.

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eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR

Project description:Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4- Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA-selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5’UTR of target mRNAs directly upstream of the AUG start codon. Conclusions: Our data support a model whereby purine motifs towards the 3’ end of the 5’UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.

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