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

Mude Shi, Hyelim Cho, Kyung Soo Inn, Aerin Yang, Zhen Zhao, Qiming Liang, Gijs A. Versteeg, Samad Amini-Bavil-Olyaee, Lai Yee Wong, Berislav V. Zlokovic, Hee Sung Park, Adolfo García-Sastre, Jae U. Jung

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

Original languageEnglish
Article number4820
JournalNature Communications
StatePublished - 5 Sep 2014


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