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

Nat Commun. 2014 Sep 5:5:4820. doi: 10.1038/ncomms5820.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • DNA Primers / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Mass Spectrometry
  • Microscopy, Confocal
  • NF-kappa B / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Plasmids / genetics
  • Polymerase Chain Reaction
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / metabolism*
  • beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

  • DNA Primers
  • NF-kappa B
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Tripartite Motif Proteins
  • beta-Transducin Repeat-Containing Proteins
  • TRIM9 protein, human
  • Ubiquitin-Protein Ligases