Ectodomain shedding of TNF-alpha is enhanced by nardilysin via activation of ADAM proteases

Biochem Biophys Res Commun. 2008 May 23;370(1):154-8. doi: 10.1016/j.bbrc.2008.03.050. Epub 2008 Mar 18.


Tumor necrosis factor-alpha (TNF-alpha) is released from cells by proteolytic cleavage of a membrane-anchored precursor. The TNF-alpha-converting enzyme (TACE/ADAM17) is the major sheddase for ectodomain shedding of TNF-alpha. At present, however, it is poorly understood how its catalytic activity is regulated. Here, we show that nardilysin (N-arginine dibasic convertase; NRDc) enhanced TNF-alpha shedding. In a cell-based shedding assay, expression of NRDc synergistically enhanced TACE-induced TNF-alpha shedding. A peptide cleavage assay in vitro showed that recombinant NRDc enhances the cleavage of TNF-alpha induced by TACE. Notably, co-incubation of NRDc completely reversed the inhibitory effect of a physiological concentration of salt on TACE's activity in vitro. Overexpression of NRDc in TACE-deficient fibroblasts resulted in an increase in the amount of TNF-alpha released. Co-expression of NRDc with ADAM10 promoted the release compared with the sole expression of ADAM10. These results suggested that NRDc enhances TNF-alpha shedding through activation of not only TACE but ADAM10. Our results indicate the involvement of NRDc in ectodomain shedding of TNF-alpha, which may be a novel target for anti-inflammatory therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors
  • ADAM Proteins / chemistry
  • ADAM Proteins / metabolism*
  • ADAM10 Protein
  • ADAM17 Protein
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • COS Cells
  • Catalysis
  • Chlorocebus aethiops
  • Enzyme Activation
  • Humans
  • Membrane Proteins / metabolism*
  • Metalloendopeptidases / chemistry
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Protein Kinase C / metabolism
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sodium Chloride / antagonists & inhibitors
  • Sodium Chloride / pharmacology
  • Tumor Necrosis Factor-alpha / chemistry
  • Tumor Necrosis Factor-alpha / metabolism*


  • Membrane Proteins
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Sodium Chloride
  • Protein Kinase C
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • Metalloendopeptidases
  • nardilysin
  • ADAM10 Protein
  • ADAM10 protein, human
  • ADAM17 Protein
  • ADAM17 protein, human