A protein that replaces the entire cellular eIF4F complex

Department of Molecular Genetics and Microbiology and the Center for Infectious Diseases & Immunity, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
The EMBO Journal (Impact Factor: 10.43). 11/2008; 27(23):3129-39. DOI: 10.1038/emboj.2008.228
Source: PubMed


The eIF4F cap-binding complex mediates the initiation of cellular mRNA translation. eIF4F is composed of eIF4E, which binds to the mRNA cap, eIF4G, which indirectly links the mRNA cap with the 43S pre-initiation complex, and eIF4A, which is a helicase necessary for initiation. Viral nucleocapsid proteins (N) function in both genome replication and RNA encapsidation. Surprisingly, we find that hantavirus N has multiple intrinsic activities that mimic and substitute for each of the three peptides of the cap-binding complex thereby enhancing the translation of viral mRNA. N binds with high affinity to the mRNA cap replacing eIF4E. N binds directly to the 43S pre-initiation complex facilitating loading of ribosomes onto capped mRNA functionally replacing eIF4G. Finally, N obviates the requirement for the helicase, eIF4A. The expression of a multifaceted viral protein that functionally supplants the cellular cap-binding complex is a unique strategy for viral mRNA translation initiation. The ability of N to directly mediate translation initiation would ensure the efficient translation of viral mRNA.

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    • "The N mRNA can be detected as early as 2 h post ANDV infection, and is the first viral RNA detected during infection [27], [28]. The N protein has several important roles in viral replication, as it encapsidates and protects viral RNA [29]–[31], and participates in initiating viral transcription and translation by binding cellular 5′ mRNA caps [32]. N protein gradient in the host cell cytoplasm also determines the switch from viral transcription to replication [33]. "
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    PLoS ONE 06/2014; 9(6):e99764. DOI:10.1371/journal.pone.0099764 · 3.23 Impact Factor
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    • "Interestingly, mRNAs carrying NMD signals were incorporated at an increased rate into Sin Nombre transcripts in human cells, and Sin Nombre N localizes with P bodies (Mir et al. 2008). This suggests potential conservation of decapping as antiviral against bunyaviruses in mammals. "
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    ABSTRACT: Bunyaviruses are an emerging group of medically important viruses, many of which are transmitted from insects to mammals. To identify host factors that impact infection, we performed a genome-wide RNAi screen in Drosophila and identified 131 genes that impacted infection of the mosquito-transmitted bunyavirus Rift Valley fever virus (RVFV). Dcp2, the catalytic component of the mRNA decapping machinery, and two decapping activators, DDX6 and LSM7, were antiviral against disparate bunyaviruses in both insect cells and adult flies. Bunyaviruses 5' cap their mRNAs by "cap-snatching" the 5' ends of poorly defined host mRNAs. We found that RVFV cap-snatches the 5' ends of Dcp2 targeted mRNAs, including cell cycle-related genes. Loss of Dcp2 allows increased viral transcription without impacting viral mRNA stability, while ectopic expression of Dcp2 impedes viral transcription. Furthermore, arresting cells in late S/early G2 led to increased Dcp2 mRNA targets and increased RVFV replication. Therefore, RVFV competes for the Dcp2-accessible mRNA pool, which is dynamically regulated and can present a bottleneck for viral replication.
    Genes & development 07/2013; 27(13):1511-25. DOI:10.1101/gad.215384.113 · 10.80 Impact Factor
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    • "The hantavirus nucleoprotein binds to the cap of viral mRNAs with higher affinity than to cellular mRNAs, because of the presence of a short conserved sequence following the cap structure . The functions of eIF4A and eIF4G are also replaced by the hantavirus nucleoprotein (Mir and Panganiban, 2008). "
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    ABSTRACT: Translation efficiency of viral mRNAs is a key factor defining both cytopathogenicity and virulence of viruses, which are entirely dependent on the cellular translation machinery to synthesize their proteins. This dependence has led them to develop different translational reprogramming strategies to ensure viral mRNAs can effectively compete with cellular mRNAs. Junin virus (JUNV) is a member of the family arenaviridae, whose mRNAs are capped but not polyadenylated. In this work we evaluated the relevance to JUNV replication of the main components of the eIF4F complex: eIF4A, eIF4GI and eIF4E. We found the viral nucleoprotein (N) of JUNV co-localized with eIF4A and eIF4GI but not with eIF4E. Moreover, N could be immunoprecipitated in association with eIF4A and eIF4GI but not with eIF4E. Accordingly, functional impairment of eIF4A as well as eIF4GI reduced JUNV multiplication. By contrast, inhibition of eIF4E did not show a significant effect on JUNV protein synthesis. A similar situation was observed for another two members of arenaviruses: Tacaribe (TCRV) and Pichinde (PICV) viruses. Finally, the nucleoproteins of JUNV, TCRV and PICV were able to interact with 7 methyl-guanosine (cap), suggesting that the independence of JUNV multiplication on eIF4E, the cap-binding protein, may be due to the replacement of this factor by N protein.
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