title: Noncanonical NF-κB activation by the oncoprotein Tio occurs through a nonconserved TRAF3-binding motif.
abstract: Members of the nuclear factor κB (NF-κB) family of transcription factors regulate many cellular functions. Activation of NF-κB signaling is commonly classified as occurring through canonical or noncanonical pathways. Most NF-κB-inducing stimuli, including the viral oncoprotein Tio, lead to a concerted activation of both NF-κB 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-κB 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-κB cascade. Furthermore, the Tio-TRAF3 interaction did not affect components of the canonical NF-κB signaling pathway or the expression of target genes; thus, Tio induced noncanonical NF-κB independently of crosstalk with the canonical pathway. Together, these data identify a distinct molecular mechanism of noncanonical NF-κB activation that should enable studies into the particular functions of this pathway.
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: Fabian
authors.initials: F
authors.lastname: Giehler
authors.forename: Arnd
authors.initials: A
authors.lastname: Kieser
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Brigitte
authors.initials: B
authors.lastname: Biesinger
mesh_terms: D020816:Amino Acid Motifs; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D018144:Rhadinovirus / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human