Nipah virus W protein harnesses nuclear 14-3-3 to inhibit NF-\u03baB-induced proinflammatory response

François Enchéry,Noémie Aurine,Branka Horvat,Denis Gerlier,Caroline Carbonnelle,Cyrille Mathieu,Chloé Journo,Mathieu Iampietro,Claire Dumont,Louis-Marie Bloyet,Rodolphe Pelissier

doi:10.1038/s42003-021-02797-5

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.

Highlights

Nipah virus (NiV) is a highly pathogenic emerging bat-borne Henipavirus that has caused numerous outbreaks with public health concerns
NiV suppresses the production of proinflammatory cytokines in infected cells and W-C-terminal domains (CTDs) plays a role in inhibiting the canonical nuclear factor-κB (NF-κB) pathway
As NiV infection is associated with a particular inflammatory response, we initially analyzed whether NiV infection in non-human primates could modulate the production of cytokines known to be under the control of NF-κB6

Summary

Introduction

Nipah virus (NiV) is a highly pathogenic emerging bat-borne Henipavirus that has caused numerous outbreaks with public health concerns. Our data suggest that the W protein increases the steady-state level of [-3] in the nucleus and 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. Immune sensors can activate the IκB kinase (IKK) complex composed of a scaffolding protein IKKγ (NEMO) and two kinases, IKKα and IKKβ When activated, these kinases phosphorylate the IκB subunit, which leads to its ubiquitination and subsequent targeting to the proteasome for degradation[4]. Once free from its inhibitor, the p65/p50 complex becomes phosphorylated, gets into a transcriptionally active state, and enters the cell nucleus[5] There, it binds to a large set of promoters to activate hundreds of different genes, including numerous cytokines[6,7]. NiV is naturally hosted by Pteropus fruit bats, which seem to control NiV infections by a mechanism still poorly understood (reviewed in ref. 16)

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