Molecular mechanisms of TRAF6 regulation and intranuclear localization (P1305)

Tumor-necrosis factor receptor associated factors (TRAFs) are widely regarded as cytoplasmic adaptor proteins, that are important for the assembly of signaling complexes necessary for cell-receptor mediated immunological response. Among the TRAFs, TRAF6 is uniquely able to couple TLR/IL-1 and TNFR activation of NF-κB. Insomuch, the regulation of TRAF6 is critical for normal cellular physiology and responses to activation events. Accumulated evidence suggests that TRAF6 is regulated by both 1) interactions with other molecules as well as 2) an intramolecular interaction with itself. We have previously reported autoinhibition by the intramolecular interaction of TRAF6’s N-terminal Ring-zinc (RZ) and C-terminal MATH domains in trans. We now provide evidence that IRAK1, which contains a TRAF-Interaction Motif (TIM), can counteract TRAF6 autoinhibition. Further, we newly identify that the transcription factor Sox4 interacts with TRAF6 and that overexpression of either Sox4 or Syntenin, a dual PDZ domain containing protein, alters TRAF6 activation of NF-κB and translocates the normally cytoplasmic TRAF6 into the nucleus. While many studies have focused on cytoplasmic TRAF6 and its activation, there are few reports on the inhibition of TRAF6 and none have provided a mechanism by which it enters the nucleus.