Nipah virus W protein harnesses nuclear 14-3-3 to inhibit NF-κB-induced proinflammatory response.

Abstract

Nipah virus (NiV) is a highly pathogenic emerging bat-borne Henipavirus that has caused numerous outbreaks with public health concerns. It is able to inhibit the host innate immune response. Since the NF-κB pathway plays a crucial role in the innate antiviral response as a major transcriptional regulator of inflammation, we postulated its implication in the still poorly understood NiV immunopathogenesis. We report here that NiV inhibits the canonical NF-κB pathway via its nonstructural W protein. Translocation of the W protein into the nucleus causes nuclear accumulation of the cellular scaffold protein 14-3-3 in both African green monkey and human cells infected by NiV. Excess of 14-3-3 in the nucleus was associated with a reduction of NF-κB p65 subunit phosphorylation and of its nuclear accumulation. Importantly, W-S449A substitution impairs the binding of the W protein to 14-3-3 and the subsequent suppression of NF-κB signaling, thus restoring the production of proinflammatory cytokines. Our data suggest that the W protein increases the steady-state level of 14-3-3 in the nucleus and consequently enhances 14-3-3-mediated negative feedback on the NF-κB pathway. These findings provide a mechanistic model of W-mediated disruption of the host inflammatory response, which could contribute to the high severity of NiV infection.

• Authors: François Enchéry, Claire Dumont, Mathieu Iampietro, Rodolphe Pelissier, Noémie Aurine, Louis-Marie Bloyet, Caroline Carbonnelle, Cyrille Mathieu, Chloé Journo, Denis Gerlier, Branka Horvat
• Journal: Communications biology (Commun Biol) Vol. 4 Issue 1 Pg. 1292 (11 16 2021) ISSN: 2399-3642 [Electronic] England
• PMID: 34785771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• NF-kappa B
• Viral Proteins
• W protein, Nipah virus

Topics

• Animals
• Cell Line
• Cell Nucleus (immunology)
• Chlorocebus aethiops
• HEK293 Cells
• HeLa Cells
• Humans
• Immunity, Innate (physiology)
• NF-kappa B
• Nipah Virus (genetics, physiology)
• Signal Transduction (immunology)
• Viral Proteins (metabolism)