Page 37 - TBE_Book_V2_2019

Chapter 2a: Virology

small membrane-associated protein, NS2B, response element (ISRE) promoters in cells
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serves as a crucial co-factor for protease stimulated with IFN. NS4A and, to a lesser
activity of the NS3 protein. The central extent, NS2A also block IFN signaling, and the
hydrophilic domain of the NS2B protein cumulative effect of these 2 proteins together
possibly interacts with the NS3 protein and it with NS4B results in robust IFN signaling
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is flanked by hydrophobic regions probably inhibition.
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anchored in the membrane. The central
NS5 is the largest (100 kDa) and most highly
hydrophilic region of NS2B (40 amino acids
conserved viral protein serving as a viral RNA-
that mediate the NS2B co-factor activity) is dependent RNA polymerase. Its C-terminus
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flanked by hydrophobic regions that mediate shares sequence homology with RNA-
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membrane association.
dependent RNA polymerases of other
NS3, the second largest viral protein, is an positive-stranded RNA viruses. 39,94 The N-
enzyme central to virus replication and poly- terminal domain has a function as AdoMet-
protein processing. Conserved regions impart dependent methyltransferase involved in the
functions as a serine protease, helicase, and mRNA capping process, transferring a methyl
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RNA nucleoside tri-phosphatase. The group from the cofactor S-adenosyl-l-
protease activity is localized at the N-terminal methionine onto the N7 atom of the cap
domain of NS3, and this enzyme cleaves guanine and onto the 2′OH group of the ribose
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peptide bonds between NS2A-NS2B, NS2B- moiety of the first RNA nucleotide. The NS5
NS3, NS3-NS4A, and NS4B-NS5. As mentioned proteins form complexes with NS3 proteins,
above, the protease activity occurs, in which results in stimulation of the NS3 RNA
association with a 40-amino acid region of nucleoside triphosphatase activity. 39,95
NS2B, resulting in the formation of a The NS5 protein is a promising target for
heterodimeric complex. 39,86 It was found that specific antiviral inhibitors. Indeed, several
mutations which were mapped in close nucleoside analogs targeting NS5 and causing
proximity to the NS2B-NS3 protease active site
premature termination of viral RNA synthesis
may determine the neuro- or non- were found to exhibit high inhibitory activity
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neuropathogenicity of TBEV. The C-terminal against TBEV. 96,97
region of the NS3 protein has a helicase
activity, utilizing the energy released from ATP Apart from the main function as RNA
to unwind RNA duplexes. Possible functions dependent RNA polymerase, the TBEV NS5
include elimination of complex secondary protein interferes with type I IFN JAK-STAT
structures of viral RNA and/or resolving RNA signaling. 98,99
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duplexes formed during replication. The C-
terminal region also has RNA triphosphatase
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and 5′RNA phosphatase activities. Due to the Replication strategy
crucial role of NS3 protein in the virus Infection of the host cell with TBEV begins
replication process, this protein represents an with the binding of the virus to a cell receptor
excellent target for the development of
86,89 (Figure 6), which has not yet been
specific antiviral inhibitors.
unequivocally identified. Interaction of the
NS4A and NS4B are small, hydrophobic viral particle with cellular receptors is
proteins. NS4A is probably part of the mediated by viral E glycoprotein. Kopecký et
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replication complex. NS4B, a trans- al. identified 2 polypeptides of 35 and 18
membrane protein localized to the sites of kDa as putative vertebrate receptors for TBEV
replication and nucleus, partially blocks using a viroblot technique with anti-idiotypic
activation of STAT1 and IFN-stimulated monoclonal antibodies directed against

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