Article

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: 10.75). 11/2008; 27(23):3129-39. DOI: 10.1038/emboj.2008.228
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
119 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The hantaviral zoonotic diseases pose significant threat to human health due to the lack of potential antiviral therapeutics or a vaccine against hantaviruses. Sin Nombre hantavirus nucleocapsid protein (N) augments mRNA translation. N binds to both the mRNA 5' cap and 40S ribosomal subunit via ribosomal protein S19 (RPS19). N with the assistance of viral mRNA 5' untranslated region (UTR) preferentially favors the translation of downstream open reading frame. We identified and characterized the RPS19 binding domain at the N-terminus of N. Its deletion did not influence the secondary structure but impacted the conformation of trimeric N molecules. N variant lacking the RPS19 binding region was able to bind both the mRNA 5' cap and panhandle like structure, formed by the termini of viral genomic RNA. In addition, N variant formed stable trimers similar to wild type N. Use of this variant in multiple experiments provided insights into the mechanism of ribosome loading during N-mediated translation strategy. Our studies suggest that N molecules individually associated with mRNA 5' cap and RPS19 of the 40S ribosomal subunit undergo N-N interaction to facilitate the engagement of N associated ribosomes at the mRNA 5' cap. These studies have revealed new targets for therapeutic intervention of hantavirus infection.
    Biochemical Journal 07/2014; 464. DOI:10.1042/BJ20140449 · 4.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Translation is a complex process involving diverse cellular proteins, including the translation initiation factor eIF4E, which has been shown to be a protein that is a point for translational regulation. Viruses require components from the host cell to complete their replication cycles. Various studies show how eIF4E and its regulatory cellular proteins are manipulated during viral infections. Interestingly, viral action mechanisms in eIF4E are diverse and have an impact not only on viral protein synthesis, but also on other aspects that are important for the replication cycle, such as the proliferation of infected cells and stimulation of viral reactivation. This review shows how some viruses use eIF4E and its regulatory proteins for their own benefit in order to spread themselves.
    Viruses 02/2015; 7(2):739-750. DOI:10.3390/v7020739 · 3.28 Impact Factor
  • Source
    Viruses 04/2015; 7(4):1987-2005. DOI:10.3390/v7041987 · 3.28 Impact Factor

Preview

Download
1 Download
Available from