RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation

J Biol Chem. 2007 Jun 8;282(23):16776-82. doi: 10.1074/jbc.M701913200. Epub 2007 Apr 20.

Abstract

Inflammation is a homeostatic mechanism that limits the effects of infectious agents. Tumor necrosis factor (TNF) and interleukin (IL)-1 are two cytokines that induce inflammation through activation of the transcription factor NF-kappaB. Various studies have suggested that two homologous and structurally related adapter proteins TAB2 and TAB3 play redundant roles in TNF- and IL-1-mediated NF-kappaB activation pathways. Both TAB2 and TAB3 contain CUE, coiled-coil, and nuclear protein localization 4 zinc finger (NZF) domains. The NZF domains of TAB2/3 are critical for TAB2/3 to bind to Lys(63)-linked polyubiquitin chains of other adaptor proteins, such as receptor-interacting protein and TRAF6, which are two signaling proteins essential for TNF- and IL-1-induced NF-kappaB activation, respectively. In a search for proteins containing NZF domains conserved with those of TAB2/3, we identified RBCK1, which has been shown to act as an E3 ubiquitin ligase in iron metabolism. Overexpression of RBCK1 negatively regulates TAB2/3-mediated and TNF- and IL-1-induced NF-kappaB activation, whereas knockdown of RBCK1 by RNA interference potentiates TNF- and IL-1-induced NF-kappaB activation. RBCK1 physically interacts with TAB2/3 and facilitates degradation of TAB2/3 through a proteasome-dependent process. Taken together, our findings suggest that RBCK1 is involved in negative regulation of inflammatory signaling triggered by TNF and IL-1 through targeting TAB2/3 for degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Base Sequence
  • DNA Primers
  • Humans
  • Hydrolysis
  • Interleukin-1 / physiology*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Molecular Sequence Data
  • NF-kappa B / physiology*
  • RNA Interference
  • Signal Transduction / physiology
  • Transcription Factors / chemistry
  • Transcription Factors / physiology*
  • Tumor Necrosis Factor-alpha / physiology*
  • Ubiquitin-Protein Ligases

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA Primers
  • Interleukin-1
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • TAB2 protein, human
  • TAB3 protein, human
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • RBCK1 protein, human
  • Ubiquitin-Protein Ligases