Institut für Klinische und Molekulare Virologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Sci Signal. 2013 Apr 23;6(272):ra27. doi: 10.1126/scisignal.2003309.
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.
核因子 κB（NF-κB）家族转录因子的成员调节许多细胞功能。NF-κB 信号的激活通常被分类为通过经典或非经典途径发生。大多数诱导 NF-κB 的刺激物，包括病毒癌蛋白 Tio，会导致 NF-κB 两条途径的协同激活；然而，这些信号级联之间在多个水平上的广泛串扰限制了区分经典和非经典作用的能力。我们表明，Tio 诱导的非经典 NF-κB 激活依赖于直接招募肿瘤坏死因子受体相关因子 3（TRAF3）的独特序列基序。通过其 TRAF3 结合基序，Tio 触发 TRAF3 从细胞质中非依赖泛素的耗竭，从而阻止 TRAF3 抑制非经典 NF-κB 级联的信号转导。此外，Tio-TRAF3 相互作用不影响经典 NF-κB 信号通路的组成部分或靶基因的表达；因此，Tio 诱导非经典 NF-κB 激活不依赖于与经典途径的串扰。总之，这些数据确定了非经典 NF-κB 激活的独特分子机制，这应该能够研究该途径的特定功能。
