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

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2014-09
Language
English
Article Type
Article
Keywords

TRIM FAMILY PROTEINS; E3 UBIQUITIN LIGASE; BETA-TRCP; SIGNALING PATHWAYS; IKK-ALPHA; DOWN-REGULATION; TNF-ALPHA; DEGRADATION; ACTIVATION; DISEASE

Citation

NATURE COMMUNICATIONS, v.5

ISSN
2041-1723
DOI
10.1038/ncomms5820
URI
http://hdl.handle.net/10203/194532
Appears in Collection
CH-Journal Papers(저널논문)
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