Research ArticleNF-κB Signaling

Noncanonical NF-κB Activation by the Oncoprotein Tio Occurs Through a Nonconserved TRAF3-Binding Motif

Sci. Signal.  23 Apr 2013:
Vol. 6, Issue 272, pp. ra27
DOI: 10.1126/scisignal.2003309

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Preventing NF-κB Pathway Crosstalk

The transcription factor NF-κB (nuclear factor κB) can be activated by so-called canonical and noncanonical pathways. Activation of the noncanonical NF-κB pathway blocks the constitutive degradation of the kinase NIK (NF-κB–inducing kinase), which leads to the generation of an NF-κB subunit required for target gene expression. The viral oncoprotein Tio mimics a constitutively active receptor upstream of NF-κB signaling, and de Jong et al. found that it contains a binding motif not conserved in other proteins that bind to TRAF3 (tumor necrosis factor receptor–associated factor 3), an inhibitor of noncanonical NF-κB signaling. This TRAF3-binding motif enabled Tio to specifically activate noncanonical NF-κB signaling without triggering crosstalk with the canonical pathway. Tio signaling did not result in TRAF3 degradation; rather, it induced the sequestration of a TRAF3-containing degradative complex from NIK to stimulate the noncanonical pathway. These data suggest that Tio might be used as a tool to examine the specific activation of genes targeted by noncanonical NF-κB signaling in the context of viral transformation.