TRIM79α, an Interferon-Stimulated Gene Product, Restricts Tick-Borne Encephalitis Virus Replication by Degrading the Viral RNA Polymerase

Abstract

In response to virus infection, type I interferons (IFNs) induce several genes, most of whose functions are largely unknown. Here we show that the tripartite motif (TRIM) protein, TRIM79α, is an IFN-stimulated gene (ISG) product that specifically targets tick-borne encephalitis virus (TBEV), a Flavivirus that causes encephalitides in humans. TRIM79α restricts TBEV replication by mediating lysosome-dependent degradation of the flavivirus NS5 protein, an RNA-dependent RNA polymerase essential for virus replication. NS5 degradation was specific to tick-borne flaviviruses as TRIM79α did not recognize NS5 from West Nile virus (WNV) or inhibit WNV replication. In the absence of TRIM79α, IFN-β was less effective in inhibiting tick-borne flavivirus infection of mouse macrophages, highlighting the importance of a single virus-specific ISG in establishing an antiviral state. The specificity of TRIM79α for TBEV reveals a remarkable ability of the innate IFN response to discriminate between closely related flaviviruses.

Serotype-specific Differences in Dengue Virus Non-structural Protein 5 Nuclear Localization

“…In addition, 2Ј-O-methylation of the viral RNA cap structure by the West Nile virus NS5 protein modulates the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (18). Specific host cells can also prevent the actions of NS5, as evi-denced by the finding that the NS5 of the tick-borne viruses Langat virus and tick-borne encephalitis virus are actively targeted for degradation by tripartite motif protein 79␣ (19).…”

Type I Interferon Protects Mice from Fatal Neurotropic Infection with Langat Virus by Systemic and Local Antiviral Responses

“…This leads to a reduced expression of antiviral ISGs. Furthermore, antiviral responses can be dampened by interference with a direct antiviral response by TRIM79␣, which specifically inhibits TBEV replication (27) or by inhibition of the positive feedback loop of IFN induction by reduced IRF-7 expression (9). However, a specific protein responsible for this inhibition by TBEV or LGTV has not yet been detected (19).…”

“…Additionally, single staining for EP and IBA1 was conducted. The following antibodies were used: mouse anti-GFAP (1:500 [Sigma]), mouse antiNeuN (1:500 [Millipore]), rabbit anti-IBA1 (1:500 [Synaptic System]), mouse anti-E protein (26), and chicken anti-NS5 protein (1:1,600) (27).…”

TRIM22 Inhibits Influenza A Virus Infection by Targeting the Viral Nucleoprotein for Degradation

“…TRIM28 restricts murine leukemia virus (MLV) as well as endogenous retroviral replication in cells of germ line origin (11). Recently, TRIM79␣ was shown to specifically restrict tick-borne encephalitis virus (12). The importance of TRIM molecules in host defense against IAV infection has been illustrated by the finding that the RING ubiquitin E3 ligase TRIM25 is crucial for RIG-I-mediated induction of type I IFNs (13), which can be directly counteracted by the IAV nonstructural protein 1 (NS1) (14).…”