Artículo
Zika virus NS4B protein targets TANK-binding kinase 1 and inhibits type I interferon production
Sarratea, Maria Belén
; Sanchez Alberti, Andrés
; Redolfi, Daniela María
; Noli Truant, Sofia
; Iannantuono López, Laura Valeria
; Bivona, Augusto Ernesto
; Mariuzza, Roy A.; Fernández, Marisa Mariel
; Malchiodi, Emilio Luis
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Fecha de publicación:
12/2023
Editorial:
Elsevier Science
Revista:
Biochimica et Biophysica Acta - General Subjects
ISSN:
0304-4165
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Background: During viral infections, nucleic acid sensing by intracellular receptors can trigger type I interferon (IFN-I) production, key mediators in antiviral innate immunity. However, many flaviviruses use non-structural proteins to evade immune sensing favoring their survival. These mechanisms remain poorly characterized. Here, we studied the role of Zika virus (ZIKV) NS4B protein in the inhibition of IFN-I induction pathway and its biophysical interaction with host proteins. Methods: Using different cell-based assays, we studied the effect of ZIKV NS4B in the activation of interferon regulatory factors (IRFs), NF-κB, cytokines secretion and the expression of interferon-stimulating genes (ISG). We also analyzed the in vitro interaction between recombinant ZIKV NS4B and TANK-binding kinase 1 (TBK1) using surface plasmon resonance (SPR). Results: Transfection assays showed that ZIKV NS4B inhibits IRFs activation involved in different nucleic acid sensing cascades. Cells expressing NS4B secreted lower levels of IFN-β and IL-6. Furthermore, early induction of ISGs was also restricted by ZIKV NS4B. For the first time, we demonstrate by SPR assays that TBK1, a critical component in IFN-I production pathway, binds directly to ZIKV NS4B (KD of 3.7 × 10−6 M). In addition, we show that the N-terminal region of NS4B is directly involved in this interaction. Conclusions: Altogether, our results strongly support that ZIKV NS4B affects nucleic acid sensing cascades and disrupts the TBK1/IRF3 axis, leading to an impairment of IFN-β production. Significance: This study provides the first biophysical data of the interaction between ZIKV NS4B and TBK1, and highlights the role of ZIKV NS4B in evading the early innate immune response.
Palabras clave:
IMMUNE EVASION
,
INTERFERON
,
ISG
,
NS4B
,
TBK1
,
ZIKA VIRUS
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Articulos(IDEHU)
Articulos de INST.DE EST.DE LA INMUNIDAD HUMORAL PROF.R.A.MARGNI
Articulos de INST.DE EST.DE LA INMUNIDAD HUMORAL PROF.R.A.MARGNI
Citación
Sarratea, Maria Belén; Sanchez Alberti, Andrés; Redolfi, Daniela María; Noli Truant, Sofia; Iannantuono López, Laura Valeria; et al.; Zika virus NS4B protein targets TANK-binding kinase 1 and inhibits type I interferon production; Elsevier Science; Biochimica et Biophysica Acta - General Subjects; 1867; 12; 12-2023; 1-14
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