CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members

Nature. 2003 Aug 14;424(6950):793-6. doi: 10.1038/nature01803.

Abstract

Familial cylindromatosis is an autosomal dominant predisposition to tumours of skin appendages called cylindromas. Familial cylindromatosis is caused by mutations in a gene encoding the CYLD protein of previously unknown function. Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis. CYLD inhibits activation of NF-kappaB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappaB. The inhibition of NF-kappaB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR-associated factor 2 (TRAF2) and, to a lesser extent, TRAF6. These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappaB that is required for appropriate cellular homeostasis of skin appendages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD40 Antigens / metabolism
  • Cell Line
  • Deubiquitinating Enzyme CYLD
  • Edar Receptor
  • Humans
  • I-kappa B Kinase
  • Membrane Proteins / metabolism
  • Mutation
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / metabolism
  • RNA Interference
  • Receptors, Ectodysplasin
  • Receptors, Tumor Necrosis Factor / metabolism*
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 6
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin / metabolism*
  • Xedar Receptor

Substances

  • CD40 Antigens
  • EDA2R protein, human
  • EDAR protein, human
  • Edar Receptor
  • Membrane Proteins
  • NF-kappa B
  • Proteins
  • Receptors, Ectodysplasin
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 6
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Xedar Receptor
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD