title: Activation of noncanonical NF-kappaB signaling by the oncoprotein Tio.
abstract: NF-kappaB transcription factors are key regulators of cellular proliferation and frequently contribute to oncogenesis. The herpesviral oncoprotein Tio, which promotes growth transformation of human T cells in a recombinant herpesvirus saimiri background, potently induces canonical NF-kappaB signaling through membrane recruitment of the ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6). Here, we show that, in addition to Tio-TRAF6 interaction, the Tio-induced canonical NF-kappaB signal requires the presence of the regulatory subunit of the inhibitor of kappaB kinase (IKK) complex, NF-kappaB essential modulator (NEMO), and the activity of its key kinase, IKKbeta, to up-regulate expression of endogenous cellular inhibitor of apoptosis 2 (cIAP2) and interleukin 8 (IL-8) proteins. Dependent on TRAF6 and NEMO, Tio enhances the expression of the noncanonical NF-kappaB proteins, p100 and RelB. Independent of TRAF6 and NEMO, Tio mediates stabilization of the noncanonical kinase, NF-kappaB-inducing kinase (NIK). Concomitantly, Tio induces efficient processing of the p100 precursor molecule to its active form, p52, as well as DNA binding of nuclear p52 and RelB. In human T cells transformed by infection with a Tio-recombinant virus, sustained expression of p100, RelB, and cIAP2 depends on IKKbeta activity, yet processing to p52 remains largely unaffected by IKKbeta inhibition. However, long term inhibition of IKKbeta disrupts the continuous growth of the transformed cells and induces cell death. Hence, the Tio oncoprotein triggers noncanonical NF-kappaB signaling through NEMO-dependent up-regulation of p100 precursor and RelB, as well as through NEMO-independent generation of p52 effector.
authors.affiliation: Institut für Klinische und Molekulare Virologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Sarah Jill
authors.initials: SJ
authors.lastname: de Jong
authors.forename: Jens-Christian
authors.initials: JC
authors.lastname: Albrecht
authors.forename: Monika
authors.initials: M
authors.lastname: Schmidt
authors.forename: Ingrid
authors.initials: I
authors.lastname: Müller-Fleckenstein
authors.forename: Brigitte
authors.initials: B
authors.lastname: Biesinger
mesh_terms: D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001665:Binding Sites; D049109:Cell Proliferation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019169:Jurkat Cells; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C491731:IKBKG protein, human; D051034:Inhibitor of Apoptosis Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; C497593:RELB protein, human; D048029:TNF Receptor-Associated Factor 6; D051841:Transcription Factor RelB; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase