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Sci. Signal., 23 April 2013
Vol. 6, Issue 272, p. ra27
[DOI: 10.1126/scisignal.2003309]


Noncanonical NF-{kappa}B Activation by the Oncoprotein Tio Occurs Through a Nonconserved TRAF3-Binding Motif

Sarah Jill de Jong1*, Jens-Christian Albrecht1, Fabian Giehler2, Arnd Kieser2, Heinrich Sticht3, and Brigitte Biesinger1{dagger}

1 Institut für Klinische und Molekulare Virologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
2 Abteilung Genvektoren, Helmholtz Zentrum München–Deutsches Forschungszentrum für Gesundheit und Umwelt, D-81377 München, Germany.
3 Institutfür Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.

* Present address: St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.

Abstract: Members of the nuclear factor {kappa}B (NF-{kappa}B) family of transcription factors regulate many cellular functions. Activation of NF-{kappa}B signaling is commonly classified as occurring through canonical or noncanonical pathways. Most NF-{kappa}B–inducing stimuli, including the viral oncoprotein Tio, lead to a concerted activation of both NF-{kappa}B pathways; however, extensive crosstalk at multiple levels between these signaling cascades restricts the ability to discriminate between the canonical and the noncanonical effects. We showed that noncanonical NF-{kappa}B activation by Tio depends on a distinct sequence motif that directly recruits tumor necrosis factor receptor–associated factor 3 (TRAF3). Through its TRAF3-binding motif, Tio triggered a ubiquitin-independent depletion of TRAF3 from the cytosol, which prevented TRAF3 from inhibiting signaling through the noncanonical NF-{kappa}B cascade. Furthermore, the Tio-TRAF3 interaction did not affect components of the canonical NF-{kappa}B signaling pathway or the expression of target genes; thus, Tio induced noncanonical NF-{kappa}B independently of crosstalk with the canonical pathway. Together, these data identify a distinct molecular mechanism of noncanonical NF-{kappa}B activation that should enable studies into the particular functions of this pathway.

{dagger} Corresponding author. E-mail: Brigitte.Biesinger{at}

Citation: S. J. de Jong, J.-C. Albrecht, F. Giehler, A. Kieser, H. Sticht, B. Biesinger, Noncanonical NF-{kappa}B Activation by the Oncoprotein Tio Occurs Through a Nonconserved TRAF3-Binding Motif. Sci. Signal. 6, ra27 (2013).

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