Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding.

Autor:	Smith RWP; Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; nicola.gray@ed.ac.uk r.smith@ed.ac.uk.; Medical Research Council Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.; Medical Research Council-University of Glasgow Centre for Virus Research, Garscube Campus, Glasgow G61 1QH, United Kingdom., Anderson RC; Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.; Medical Research Council Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom., Larralde O; Medical Research Council-University of Glasgow Centre for Virus Research, Garscube Campus, Glasgow G61 1QH, United Kingdom., Smith JWS; Medical Research Council Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom., Gorgoni B; Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.; Medical Research Council Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom., Richardson WA; Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.; Medical Research Council Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom., Malik P; Medical Research Council-University of Glasgow Centre for Virus Research, Garscube Campus, Glasgow G61 1QH, United Kingdom.; Wellcome Trust Centre for Cell Biology and Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, United Kingdom., Graham SV; Medical Research Council-University of Glasgow Centre for Virus Research, Garscube Campus, Glasgow G61 1QH, United Kingdom., Gray NK; Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; nicola.gray@ed.ac.uk r.smith@ed.ac.uk.; Medical Research Council Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Jun 13; Vol. 114 (24), pp. 6310-6315. Date of Electronic Publication: 2017 May 30.
DOI:	10.1073/pnas.1610417114
Abstrakt:	Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP-eIF4G-eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27-PABP-eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP-eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non-poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP-eIF4G complex in translation initiation. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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