Biochemistry and Pharmacology - Research Publications

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Type: Journal Article × Start date: 2012 × End date: 2012 × Author: Moseley, Gregory ×

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    Editorial: Subcellular trafficking of pathogens: targeting for therapeutics.
    Moseley, GW ; JANS, D (Bentham Science Publishers, 2012)
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    Subcellular trafficking in rhabdovirus infection and immune evasion: a novel target for therapeutics.
    Oksayan, S ; Ito, N ; Moseley, G ; Blondel, D (Bentham Science Publishers Ltd., 2012-02)
    Vesicular stomatitis virus (VSV) and Rabies Virus (RABV) are the prototypic members of the rhabdovirus family. These viruses have a particularly broad host range, and despite the availability of vaccines, RABV still causes more than 50,000 human deaths a year. Trafficking of the virion or viral particles is important at several stages of the replicative life cycle, including cellular entry, localization into the cytoplasmic inclusion bodies which primarily house the transcription and replication of the viral genome, and migration to the plasma membrane from whence the virus is released by budding. Intriguingly, specific viral proteins, VSV M and RABV P have also been shown to undergo intracellular trafficking independent of the other viral apparatus. These proteins are multifunctional, and play roles in antagonism of host processes, namely the IFN system, and as such enable viral evasion of the innate cellular antiviral response. A body of recent research has been aimed at characterizing the mechanisms by which these proteins are able to shuttle between and localize to various subcellular sites, including the nucleus, which is not required during the cytoplasmic replicative life cycle of the virus. This work has indicated that trafficking of these proteins plays a significant role in determining the ability of the viruses to replicate and cause infection, and as such, represents a viable target for development of a new generation of vaccines and prophylactic therapeutics which are required to battle these pathogens of human and agricultural significance.
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    Viral Interferon Antagonism: Making the Leap from the Bench to the Clinic
    W. Moseley, G (OMICS Publishing Group, 2012)
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    A Novel Nuclear Trafficking Module Regulates the Nucleocytoplasmic Localization of the Rabies Virus Interferon Antagonist, P Protein
    Oksayan, S ; Wiltzer, L ; Rowe, CL ; Blondel, D ; Jans, DA ; Moseley, GW (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2012-08-10)
    Regulated nucleocytoplasmic transport of proteins is central to cellular function and dysfunction during processes such as viral infection. Active protein trafficking into and out of the nucleus is dependent on the presence within cargo proteins of intrinsic specific modular signals for nuclear import (nuclear localization signals, NLSs) and export (nuclear export signals, NESs). Rabies virus (RabV) phospho (P) protein, which is largely responsible for antagonising the host anti-viral response, is expressed as five isoforms (P1-P5). The subcellular trafficking of these isoforms is thought to depend on a balance between the activities of a dominant N-terminal NES (N-NES) and a distinct C-terminal NLS (C-NLS). Specifically, the N-NES-containing isoforms P1 and P2 are cytoplasmic, whereas the shorter P3-P5 isoforms, which lack the N-NES, are believed to be nuclear through the activity of the C-NLS. Here, we show for the first time that RabV P contains an additional strong NLS in the N-terminal region (N-NLS), which, intriguingly, overlaps with the N-NES. This arrangement represents a novel nuclear trafficking module where the N-NLS is inactive in P1 but becomes activated in P3, concomitant with truncation of the N-NES, to become the principal targeting signal conferring nuclear accumulation. Understanding this unique switch arrangement of overlapping, co-regulated NES/NLS sequences is vital to delineating the critical role of RabV P protein in viral infection.
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    Conservation of a Unique Mechanism of Immune Evasion across the Lyssavirus Genus
    Wiltzer, L ; Larrous, F ; Oksayan, S ; Ito, N ; Marsh, GA ; Wang, LF ; Blondel, D ; Bourhy, H ; Jans, DA ; Moseley, GW (AMER SOC MICROBIOLOGY, 2012-09)
    The evasion of host innate immunity by Rabies virus, the prototype of the genus Lyssavirus, depends on a unique mechanism of selective targeting of interferon-activated STAT proteins by the viral phosphoprotein (P-protein). However, the immune evasion strategies of other lyssaviruses, including several lethal human pathogens, are unresolved. Here, we show that this mechanism is conserved between the most distantly related members of the genus, providing important insights into the pathogenesis and potential therapeutic targeting of lyssaviruses.