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Structural Studies of the Eif4e–Vpg Complex Reveal a Direct Competition for Capped RNA: Implications for Translation

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Structural Studies of the Eif4e–Vpg Complex Reveal a Direct Competition for Capped RNA: Implications for Translation Structural studies of the eIF4E–VPg complex reveal a direct competition for capped RNA: Implications for translation Luciana Coutinho de Oliveiraa,1,2, Laurent Volpona,1, Amanda K. Rahardjoa, Michael J. Osbornea, Biljana Culjkovic-Kraljacica, Christian Trahanb, Marlene Oeffingerb,c,d, Benjamin H. Kwoka, and Katherine L. B. Bordena,3 aInstitute of Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Pavilion Marcelle-Coutu, Chemin Polytechnique, Montréal, QC H3T 1J4, Canada; bDepartment for Systems Biology, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; cDépartement de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3T 1J4, Canada; and dDivision of Experimental Medicine, McGill University, Montréal, QC H3A 1A3, Canada Edited by Lynne E. Maquat, University of Rochester School of Medicine and Dentistry, Rochester, NY, and approved October 16, 2019 (received for review March 19, 2019) Viruses have transformed our understanding of mammalian RNA of eIF4E can be targeted in patients to provide clinical benefit, processing, including facilitating the discovery of the methyl-7- highlighting its critical importance. guanosine (m7G)caponthe5′ end of RNAs. The m7Gcapisrequired Viruses have paved the way for our understanding of many for RNAs to bind the eukaryotic translation initiation factor eIF4E aspects of host-cell RNA processing, including m7G capping. and associate with the translation machinery across plant and ani- Indeed, studies into cytoplasmic polyhedrosis virus (CPV) infec- mal kingdoms. The potyvirus-derived viral genome-linked protein tion in silkworm and vaccinia virus (VV) in mammalian cells were (VPg) is covalently bound to the 5′ end of viral genomic RNA (gRNA) critical for the elucidation of the m7G cap structure over 40 y ago and associates with host eIF4E for successful infection. Divergent (3, 14, 15). Here, we exploited unusual features of potyvirus bio- models to explain these observations proposed either an un- chemistry to unearth unknown strategies that can be implemented known mode of eIF4E engagement or a competition of VPg for to engage eIF4E. Potyviruses are members of the picorna-like 7 the m G cap-binding site. To dissect these possibilities, we resolved plant viruses. Their infection of mainstay crops has devastating the structure of VPg, revealing a previously unknown 3-dimensional economic consequences (16). Genetic studies revealed that poty- BIOCHEMISTRY – (3D) fold, and characterized the VPg eIF4E complex using NMR and viruses require host-cell translation machinery to replicate, and biophysical techniques. VPg directly bound the cap-binding site of 7 specifically, these reports have associated the potyviral protein eIF4E and competed for m G cap analog binding. In human cells, VPg genome linked (viral genome-linked protein [VPg]) with host plant inhibited eIF4E-dependent RNA export, translation, and oncogenic eIF4E (17–21). Indeed, mutations in plant eIF4E are associated transformation. Moreover, VPg formed trimeric complexes with eIF4E–eIF4G, eIF4E bound VPg–luciferase RNA conjugates, and these VPg–RNA conjugates were templates for translation. Infor- Significance matic analyses revealed structural similarities between VPg and the human kinesin EG5. Consistently, EG5 directly bound eIF4E in a sim- RNA processing including covalent modifications (e.g., the ad- 7 ilar manner to VPg, demonstrating that this form of engagement is dition of the methyl-7-guanosine [m G] “cap” on the 5′ end of relevant beyond potyviruses. In all, we revealed an unprecedented transcripts) centrally influences the proteome. For example, 7 modality for control and engagement of eIF4E and show that VPg– eIF4E recruits RNAs for translation by binding the m G cap. RNA conjugates functionally engage eIF4E. As such, potyvirus VPg eIF4E is engaged and controlled by the binding of factors to its 7 provides a unique model system to interrogate eIF4E. dorsal surface while leaving its m G cap-binding site free for RNA recruitment. Here, we unexpectedly found that a small VPg | m7 cap | potyvirus | translation | eIF4E viral protein, viral genome-linked protein (VPg), directly binds the cap-binding site of eIF4E, indicating that eIF4E can addi- tionally be controlled through direct competition with its cap- he eukaryotic translation initiation factor eIF4E plays important binding site. Furthermore, VPg–RNA conjugates also bind eIF4E Troles in posttranscriptional control in plant and animals (1). Its 7 and are templates for translation, suggesting that VPg may association with the methyl-7-guanosine (m G) “cap” on the 5′ end 7 substitute for the m G cap during infection. of RNAs allows eIF4E to recruit transcripts to the RNA processing 7 machinery (2). To date, the m G cap is generally accepted as the Author contributions: L.C.d.O., L.V., M.J.O., B.C.-K., C.T., M.O., B.H.K., and K.L.B.B. de- universal 5′ adaptor for RNAs in eukaryotes (3), with the exception signed research; L.C.d.O., L.V., A.K.R., M.J.O., B.C.-K., C.T., and K.L.B.B. performed re- i 3 search; L.V., M.J.O., B.C.-K., B.H.K., and K.L.B.B. contributed new reagents/analytic tools; of ( ) the structurally related m G cap, which is also used by L.C.d.O., L.V., A.K.R., M.J.O., B.C.-K., C.T., and K.L.B.B. analyzed data; and L.C.d.O., L.V., nematodes (4), and (ii) with lower-frequency, nicotinamide ade- M.J.O., B.C.-K., C.T., M.O., and K.L.B.B. wrote the paper. nine dinucleotide (NAD) and related analogs that destabilize The authors declare no competing interest. transcripts and thus, are probably not involved in active translation This article is a PNAS Direct Submission. 7 (5). Through its m G cap-binding activity, eIF4E recruits specific Published under the PNAS license. transcripts to the translation machinery in the cytoplasm and Data deposition: The NMR, atomic coordinates, chemical shifts, and restraints reported in promotes the nuclear export of selected RNAs from the nucleus (6, the paper have been deposited in the Biological Magnetic Resonance Data Bank (http:// www.bmrb.wisc.edu/; accession no. 27506) and the Protein Data Bank (https://www.rcsb. 7). Both activities contribute to modulation of the proteome and in org; ID code 6NFW). mammals, to its oncogenic activity (6, 7). For instance, eIF4E is 1L.C.d.O. and L.V. contributed equally to this work. dysregulated in many human cancers (6). In humans, targeting 2Present address: NMX Research and Solutions Inc., Laval, QC H7V 5B7, Canada. eIF4E with a cap competitor, the guanosine analog ribavirin, 3To whom correspondence may be addressed. Email: [email protected]. impairs its biochemical activities correlating with clinical re- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. sponses in early-phase trials in leukemia, prostate, head, and 1073/pnas.1904752116/-/DCSupplemental. neck cancers among others (8–13). Thus, the cap-binding activity www.pnas.org/cgi/doi/10.1073/pnas.1904752116 PNAS Latest Articles | 1of10 Downloaded by guest on September 27, 2021 with potyviral resistance (18–20). VPgs exist in other virus families, constructs and purified these from the soluble fraction with the such as poliovirus (22). The VPg designation is based on the co- quality of the proteins confirmed by SDS/PAGE (Sodium Dodecyl valent linkage of viral RNA to VPg. For the case of potyviruses, Sulphate-PolyAcrylamide Gel Electrophoresis) (Fig. 1C) (34), the 5′ end of the genomic RNA (gRNA) is covalently attached to NMR (Fig. 1D and SI Appendix, Fig. S2), and mass spectrometry the hydroxyl of tyrosine 64 (potato virus Y [PVY] numbering) (23– (MS) (SI Appendix,Fig.S3A). We recently reported the NMR 25). The genetic interaction between VPg and eIF4E is only assignments for a VPg construct in which the first 37 residues were reported for potyviruses (20), while other virus families typically removed to improve stability (VPgΔ37) (34). Here, the 3- use these RNA conjugates for replication (22). Consistent with dimensional (3D) solution structure of this construct was de- this, potyviral VPgs only show significant sequence homology with termined by using an automated procedure for iterative nuclear each other and not with VPgs from other families (SI Appendix, Overhauser effect (NOE) assignment using CYANA (35). The Fig. S1). structure of VPg is shown in Fig. 1 A and B and SI Appendix, Fig. While genetic studies linked VPg and eIF4E, conclusions from S3B, and the structural statistics are in SI Appendix,TableS1.The biochemical studies were highly divergent, leaving the mecha- rmsd for the ordered regions was 0.68 Å for the backbone atoms nism as to how VPg coopts eIF4E activity unsettled. Some groups of the top 20 structures. reported that PVY VPg binds m7Gcap–eIF4E–eIF4G, forming The VPg structure is unlike the previously proposed models. a quaternary complex, which suggests that VPg utilizes a novel VPgΔ37 adopts a well-folded core as well as 2 substantial un- surface on eIF4E for binding and thereby, engaging its activity (17, structured regions at the N and C termini (residues 38 to 70) and a 26). Supporting this model, mutation of the cap-binding site in flexible loop between β4- and β5-strands (residues 145 to 165) (Fig. wheat eIF4E (W123A, W102 in human eIF4E) did not reduce the 1A and SI Appendix,Fig.S3B). We note that VPg is not an ability of eIF4E to bind VPg but did reduce binding to the 7- intrinsically disordered protein. Specifically, there were many long- methylguanosine diphosphate (m7GDP) cap analog. This sug- range NOEs, indicating a tertiary structure (SI Appendix,Table gested that VPg bound to a part of eIF4E not previously known to S1), and furthermore, values for the 15N-1H heteronuclear NOE be involved in its control or engagement (26).
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