20980497
not annotated - annotated - LINNAEUS only
A vaccinia virus deletion mutant reveals the presence of additional inhibitors of NF-kappaB.
The classical nuclear factor kappa B (NF-kappaB) signaling pathway is an important regulator of inflammation and innate immunity that is activated by a wide variety of stimuli, including virus infection, tumor necrosis factor alpha (TNF-alpha), and interleukin 1Beta (IL-1Beta). Poxviruses, including vaccinia virus (VV) and ectromelia virus, encode multiple proteins that function in immune evasion. Recently, a growing number of genes encoded by poxviruses have been shown to target and disrupt the NF-kappaB signaling pathway. To determine if additional gene products that interfere with NF-kappaB signaling existed, we used a vaccinia virus deletion mutant, VV811, which is missing 55 open reading frames lacking all known inhibitors of TNF-alpha-induced NF-kappaB activation. Immunofluorescence analysis of HeLa cells treated with TNF-alpha and IL-1Beta revealed that NF-kappaB translocation to the nucleus was inhibited in VV811-infected cells. This was further confirmed through Western blotting of cytoplasmic and nuclear extracts for NF-kappaB. Additionally, VV811 infection inhibited TNF-alpha-induced IkappaBalpha degradation. In contrast to vaccinia virus strain Copenhagen (VVCop)-infected cells, VV811 infection resulted in the dramatic accumulation of phosphorylated IkappaBalpha. Correspondingly, coimmunoprecipitation assays demonstrated that the NF-kappaB-inhibitory IkappaBalpha-p65-p50 complex was intact in VV811-infected cells. Significantly, cells treated with 1-Beta-d-arabinofuranosylcytosine, an inhibitor of poxvirus late gene expression, demonstrated that an additional vaccinia virus late gene was involved in the stabilization of IkappaBalpha. Overall, this work indicates that unidentified inhibitors of NF-kappaB exist in vaccinia virus. The complex inhibition of NF-kappaB by vaccinia virus illustrates the importance of NF-kappaB activation in the antiviral response.
Ann file
T1 Species 2 16 vaccinia virus
N1 Reference T1 Taxonomy:10245
T2 Species 396 410 vaccinia virus
N2 Reference T2 Taxonomy:10245
T3 Species 412 414 VV
N3 Reference T3 Taxonomy:10245
T4 Species 420 436 ectromelia virus
N4 Reference T4 Taxonomy:12643
T5 Species 725 739 vaccinia virus
N5 Reference T5 Taxonomy:10245
T6 Species 1248 1280 vaccinia virus strain Copenhagen
N6 Reference T6 Taxonomy:10245
T7 Species 1282 1287 VVCop
N7 Reference T7 Taxonomy:10245
T8 Species 1693 1707 vaccinia virus
N8 Reference T8 Taxonomy:10245
T9 Species 1849 1863 vaccinia virus
N9 Reference T9 Taxonomy:10245
T10 Species 1904 1918 vaccinia virus
N10 Reference T10 Taxonomy:10245