Herpes Simplex Virus 1 Inhibits TANK-Binding Kinase 1 through Formation of the Us11-Hsp90 Complex.

Liu, Xing; Main, David; Ma, Yijie; He, Bin

Liu, Xing; Main, David; Ma, Yijie; He, Bin.

Afiliación

Liu X; Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Main D; Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Ma Y; Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
He B; Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA tshuo@uic.edu.

J Virol ; 92(14)2018 07 15.

Article en En | MEDLINE | ID: mdl-29743370

RESUMEN

The Us11 protein of herpes simplex virus 1 (HSV-1) is an accessory factor with multiple functions. In virus-infected cells, it inhibits double-stranded RNA-dependent protein kinase (PKR), 2',5'-oligoadenylate synthetase, RIG-I, and MDA-5. However, its precise role is incompletely defined. By screening a human cDNA library, we showed that the Us11 protein targets heat shock protein 90 (Hsp90), which inactivates TANK binding kinase 1 (TBK1) and antiviral immunity. When ectopically expressed, HSV-1 Us11 precludes TBK1 from access to Hsp90 and interferon (IFN) promoter activation. Consistently, the Us11 protein, upon HSV infection, suppresses the expression of beta interferon (IFN-ß), RANTES, and interferon-stimulated genes. This is mirrored by a blockade in the phosphorylation of interferon regulatory factor 3. Mechanistically, the Us11 protein associates with endogenous Hsp90 to disrupt the Hsp90-TBK1 complex. Furthermore, Us11 induces destabilization of TBK1 through a proteasome-dependent pathway. Accordingly, Us11 expression facilitates HSV growth. In contrast, TBK1 expression restricts viral replication. These results suggest that control of TBK1 by Us11 promotes HSV-1 infection.IMPORTANCE TANK binding kinase 1 plays a key role in antiviral immunity. Although multiple factors are thought to participate in this process, the picture is obscure in herpes simplex virus infection. We demonstrated that the Us11 protein of HSV-1 forms a complex with heat shock protein 90, which inactivates TANK binding kinase 1 and IFN induction. As a result, expression of the Us11 protein promotes HSV replication. These experimental data provide a new insight into the molecular network of virus-host interactions.

Asunto(s)

Proteínas HSP90 de Choque Térmico/metabolismo; Herpes Simple/virología; Herpesvirus Humano 1/patogenicidad; Interacciones Huésped-Patógeno; Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores; Proteínas de Unión al ARN/metabolismo; Proteínas Virales/metabolismo; Replicación Viral; Animales; Chlorocebus aethiops; Fibroblastos/citología; Fibroblastos/metabolismo; Fibroblastos/virología; Células HEK293; Herpes Simple/metabolismo; Humanos; Factor 3 Regulador del Interferón/metabolismo; Ratones; Fosforilación; Unión Proteica; Transducción de Señal; Células Vero

Palabras clave

TANK binding kinase 1; herpes simplex virus; interferons; viral replication; virus-host interactions

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Virales / Replicación Viral / Proteínas de Unión al ARN / Proteínas Serina-Treonina Quinasas / Herpesvirus Humano 1 / Proteínas HSP90 de Choque Térmico / Interacciones Huésped-Patógeno / Herpes Simple Límite: Animals / Humans Idioma: En Revista: J Virol Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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