Negative regulation of NF-κB activity by brain-specific TRIpartite Motif protein 9

The TRIpartite Motif (TRIM) family of RING-domain-containing proteins participate in a variety of cellular functions. The beta-transducin repeat-containing protein (beta-TrCP), a component of the Skp-Cullin-F-box-containing (SCF) E3 ubiquitin ligase complex, recognizes the NF-kappa B inhibitor I kappa B alpha and precursor p100 for proteasomal degradation and processing, respectively. beta-TrCP thus plays a critical role in both canonical and non-canonical NF-kappa B activation. Here we report that TRIM9 is a negative regulator of NF-kappa B activation. Interaction between the phosphorylated degron motif of TRIM9 and the WD40 repeat region of beta-TrCP prevented beta-TrCP from binding its substrates, stabilizing I kappa B alpha and p100 and thereby blocking NF-kappa B activation. Consequently, expression or depletion of the TRIM9 gene significantly affected NF-kappa B-induced inflammatory cytokine production. This study not only elucidates a mechanism for TRIM9-mediated regulation of the beta-TrCP SCF complex activity but also identifies TRIM9 as a brain-specific negative regulator of the NF-kappa B pro-inflammatory signalling pathway.