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Review
. 2017 Jan 18;91(3):e01970-16.
doi: 10.1128/JVI.01970-16. Print 2017 Feb 1.

The Many Faces of the Flavivirus NS5 Protein in Antagonism of Type I Interferon Signaling

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Free PMC article
Review

The Many Faces of the Flavivirus NS5 Protein in Antagonism of Type I Interferon Signaling

Sonja M Best. J Virol. .
Free PMC article

Abstract

The vector-borne flaviviruses cause severe disease in humans on every inhabited continent on earth. Their transmission by arthropods, particularly mosquitoes, facilitates large emergence events such as witnessed with Zika virus (ZIKV) or West Nile virus in the Americas. Every vector-borne flavivirus examined thus far that causes disease in humans, from dengue virus to ZIKV, antagonizes the host type I interferon (IFN-I) response by preventing JAK-STAT signaling, suggesting that suppression of this pathway is an important determinant of infection. The most direct and potent viral inhibitor of this pathway is the nonstructural protein NS5. However, the mechanisms utilized by NS5 from different flaviviruses are often quite different, sometimes despite close evolutionary relationships between viruses. The varied mechanisms of NS5 as an IFN-I antagonist are also surprising given that the evolution of NS5 is restrained by the requirement to maintain function of two enzymatic activities critical for virus replication, the methyltransferase and RNA-dependent RNA polymerase. This review discusses the different strategies used by flavivirus NS5 to evade the antiviral effects of IFN-I and how this information can be used to better model disease and develop antiviral countermeasures.

Keywords: JAK-STAT; NS5; West Nile virus; Zika virus; antagonism; dengue virus; flavivirus; interferons; tick-borne encephalitis virus; yellow fever virus.

Figures

FIG 1
FIG 1
Varied mechanisms of NS5-mediated antagonism of IFN-I-dependent signaling in flavivirus-infected cells. (A) The NS5 proteins of DENV, ZIKV, and YFV all bind to STAT2. Binding of STAT2 by DENV or ZIKV NS5 results in STAT2 degradation, whereas YFV NS5 requires IFN-I stimulation to “activate” the antagonist functions of NS5 (depicted by a lightning bolt) resulting in loss of transcriptional activity of ISGF3. Each of these three NS5 proteins utilizes a different E3 ubiquitin ligase in order to antagonize IFN-I signaling (TRIM23, UBR4, or a yet-to-be-identified ligase). The NS5 proteins of TBEV, LGTV, and WNV suppress maturation of the IFN-I receptor subunit IFNAR1 by binding to prolidase (PEPD). (B) Antagonism of JAK-STAT signaling by WNV in mosquitoes involves the host protein cullin 4 (CUL4) to degrade STAT via the proteasome.
FIG 2
FIG 2
Structural features of flavivirus NS5 implicated in IFN-I antagonism. (A) Surface-exposed residues of the RdRp domain of WNV (PDB ID 2HCN) are depicted in green, with amino acids important for function of NS5 from WNV, LGTV, and TBEV shown in yellow. The S/F653 residue that determines relative IFN-I antagonism and efficiency of IFNAR1 downregulation in WNV is shown in red. (B) Structure of DENV NS5 that has been rotated 90° in relation to that shown in panel A. The surface-exposed residues of the MTase domain are depicted in blue. The N-terminal 10 amino acids that are important to the function of both DENV and YFV NS5 are shown in magenta. Putative binding regions for human STAT2 on DENV NS5 are shown in light pink. The full-length structure is based on the DENV-4 NS5 crystal structure (PDB ID 5DTO) (24) with images colorized using PyMol. (C) Phylogenetic tree of NS5 sequences discussed in the text. (D) Sequence alignment showing the N-terminal 10 amino acids and the two noncontiguous regions involved in IFN-I antagonism by WNV, LGTV, and TBEV. Residues are color coded according to similar chemistries. Individual amino acids of particular importance are indicated by the colored circles below the alignment for YFV (yellow), WNV (blue), or LGTV and TBEV (orange).

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