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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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Project description:Transmissible gastroenteritis virus (TGEV) infection causes acute enteritis in swine of all ages, and especially in suckling piglets. Small intestinal inflammation is considered a central event in the pathogenesis of TGEV infections, and nuclear factor-kappa B (NF-κB) is a key transcription factor in the inflammatory response. However, it is unclear whether NF-κB is crucial for inducing inflammation during a TGEV infection. Our results show that NF-κB was activated in swine testicular (ST) cells and intestinal epithelial cell lines J2 (IPEC-J2) cells infected with TGEV, which is consistent with the up-regulation of pro-inflammatory cytokines. Treatment of TGEV-infected ST cells and IPEC-J2 cells with the NF-κB-specific inhibitor caused the down-regulation of pro-inflammatory cytokine expression, but did not significantly affect TGEV replication. Individual TGEV protein screening results demonstrated that Nsp2 exhibited a high potential for activating NF-κB and enhancing the expression of pro-inflammatory cytokines. Functional domain analyzes indicated that the first 120 amino acid residues of Nsp2 were essential for NF-κB activation. Taken together, these data suggested that NF-κB activation was a major contributor to TGEV infection-induced inflammation, and that Nsp2 was the key viral protein involved in the regulation of inflammation, with amino acids 1-120 playing a critical role in activating NF-κB. Abbreviations: TCID50: 50% tissue culture infectious dose; DMEM: Dulbecco's Modified Eagle Medium; eNOS: Endothelial nitric oxide synthase; FBS: fetal bovine serum; IFA: Indirect immunofluorescence; IκB: inhibitor of nuclear factor kappa-B; IL: interleukin; IPEC-J2: intestinal epithelial cell lines J2; IKK: IκB kinase; Luc: luciferase reporter gene; mAbs: monoclonal antibodies; MOI: multiple of infection; Nsp: nonstructural protein; NF-κB: nuclear factor-kappa ; ORFs: open reading frames; PBS: phosphate-buffered saline; p65 p-p65: phosphorylated; RT-PCR: reverse transcription PC; SeV: Sendai virus; ST: swine testicular; TGEV: Transmissible gastroenteritis virus; TNF-α: tumor necrosis factor α; UV-TGEV: Ultraviolet light-inactivated TGEV; ZnF: zinc finger.

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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