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NF-?B activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-?B activation.

ABSTRACT: Vaccinia virus protein A49 inhibits NF-?B activation by molecular mimicry and has a motif near the N terminus that is conserved in I?B?, ?-catenin, HIV Vpu, and some other proteins. This motif contains two serines, and for I?B? and ?-catenin, phosphorylation of these serines enables recognition by the E3 ubiquitin ligase ?-TrCP. Binding of I?B? and ?-catenin by ?-TrCP causes their ubiquitylation and thereafter proteasome-mediated degradation. In contrast, HIV Vpu and VACV A49 are not degraded. This paper shows that A49 is phosphorylated at serine 7 but not serine 12 and that this is necessary and sufficient for binding ?-TrCP and antagonism of NF-?B. Phosphorylation of A49 S7 occurs when NF-?B signaling is activated by addition of IL-1? or overexpression of TRAF6 or IKK?, the kinase needed for I?B? phosphorylation. Thus, A49 shows beautiful biological regulation, for it becomes an NF-?B antagonist upon activation of NF-?B signaling. The virulence of viruses expressing mutant A49 proteins or lacking A49 (v?A49) was tested. v?A49 was attenuated compared with WT, but viruses expressing A49 that cannot bind ?-TrCP or bind ?-TrCP constitutively had intermediate virulence. So A49 promotes virulence by inhibiting NF-?B activation and by another mechanism independent of S7 phosphorylation and NF-?B antagonism. Last, a virus lacking A49 was more immunogenic than the WT virus.

SUBMITTER: Neidel S

PROVIDER: S-EPMC6431142 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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NF-κB activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-κB activation.

Neidel Sarah S Ren Hongwei H Torres Alice A AA Smith Geoffrey L GL

Proceedings of the National Academy of Sciences of the United States of America 20190228 12

Vaccinia virus protein A49 inhibits NF-κB activation by molecular mimicry and has a motif near the N terminus that is conserved in IκBα, β-catenin, HIV Vpu, and some other proteins. This motif contains two serines, and for IκBα and β-catenin, phosphorylation of these serines enables recognition by the E3 ubiquitin ligase β-TrCP. Binding of IκBα and β-catenin by β-TrCP causes their ubiquitylation and thereafter proteasome-mediated degradation. In contrast, HIV Vpu and VACV A49 are not degraded. T ...[more]

PMID: 30819886

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Dataset Information

NF-?B activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-?B activation.

Publications

NF-κB activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-κB activation.

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