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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. In a study using both human cells and the African green monkeys, Enchery et al report that the highly pathogenic bat-borne Nipah virus (NiV), inhibits the NF-κB pathway via its nonstructural W protein. They demonstrate that it exerts this effect by causing nuclear accumulation of the cellular scaffold protein 14-3-3, which sheds light on pathomechanism of NiV infection.

SUBMITTER: Enchery F 

PROVIDER: S-EPMC8595879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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