Negative regulation of NF-?B activity by brain-specific TRIpartite Motif protein 9.

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

SUBMITTER: Shi M 

PROVIDER: S-EPMC4157316 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature