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Chapter 7 : Interferons and Antiviral Action
Category: Viruses and Viral Pathogenesis; Microbial Genetics and Molecular Biology
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Viruses and their hosts have evolved to coexist by maintaining viral homeostasis. At the organism level, the immune system of the host plays a major role in clearing the infection or driving the viruses to enter a latent phase. In addition to the direct action of the cells of the immune system, various cytokines, most importantly the interferons (IFNs) system, produced by them are critically important in this process. The majority of the interferon-stimulated genes (ISGs) that are induced by IFN, double-stranded RNA (dsRNA), and viruses contain IFN-stimulated response elements (ISREs) in their promoters. The usual mechanism calls for inhibition of several steps of viral gene expression through the actions of several ISG products. ISG-encoded proteins have been chosen because of the diversity of their functions and their perceived importance in mediating antiviral actions. Protein kinase RNA regulated (PKR) was one of the earliest antiviral ISGs identified and is one of the most thoroughly investigated to date. PKR has been implicated in regulation of apoptosis both in the presence and absence of viral infection. The importance of PKR in mediating antiviral actions of IFN is manifested by the variety of strategies used by different viruses to evade PKR’s activation or action. The common structural features of adenosine deaminase acting on RNA (ADAR) family proteins include a dsRNA-binding domain and a conserved cytidine deaminase domain at the carboxyl terminus that contains highly conserved residues thought to be involved in catalysis.
PKR structure and activation. (A) PKR contains two dsRNA-binding domains at its amino terminus and a kinase domain at its carboxyl terminus ( 126 ). (B) Binding of dsRNA facilitates dimerization and autophosphorylation of PKR on Thr-446 and Thr-451. Autophosphorylation activates PKR, allowing it to phosphorylate eIF2α, thereby preventing protein translation ( 82 ).
PACT structure and activation. (A) PACT contains two dsRNA-binding domains that also bind PKR and a third domain that is only involved in interaction with PKR. Numbers indicate amino acid sequence number ( 96 ). (B) Interaction of PACT-domain 3 with the PACT-binding motif present in the kinase domain of PKR disrupts the intramolecular interaction maintaining PKR in a latent state and leads to its activation ( 74 ).
Arrangement of TPR motifs in p56 proteins. Corresponding members of the p56 family in different species have similar numbers of TPR motifs located in similar locations in the linear amino acid sequence of the protein ( 110 ).
Inhibition of protein translation by p56 family members. Human and mouse p56 and p54 bind to different subunits of eIF3, inhibiting different points of the protein translation initiation process. Human p56 and human p54 bind to eIF3e and prevent formation of the ternary complex required for translation, while murine p54 and p56 bind to eIF3c and prevent assembly of the 48S preinitiation complex. Human p54 can bind to both eIF3c and eIF3e. (Adapted from reference 110 .)