CSN-mediated deneddylation differentially modulates Ci(155) proteolysis to promote Hedgehog signalling responses

Nat Commun. 2011 Feb 8;2:182. doi: 10.1038/ncomms1185.

Abstract

The Hedgehog (Hh) morphogen directs distinct cell responses according to its distinct signalling levels. Hh signalling stabilizes transcription factor cubitus interruptus (Ci) by prohibiting SCF(Slimb)-dependent ubiquitylation and proteolysis of Ci. How graded Hh signalling confers differential SCF(Slimb)-mediated Ci proteolysis in responding cells remains unclear. Here, we show that in COP9 signalosome (CSN) mutants, in which deneddylation of SCF(Slimb) is inactivated, Ci is destabilized in low-to-intermediate Hh signalling cells. As a consequence, expression of the low-threshold Hh target gene dpp is disrupted, highlighting the critical role of CSN deneddylation on low-to-intermediate Hh signalling response. The status of Ci phosphorylation and the level of E1 ubiquitin-activating enzyme are tightly coupled to this CSN regulation. We propose that the affinity of substrate-E3 interaction, ligase activity and E1 activity are three major determinants for substrate ubiquitylation and thereby substrate degradation in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COP9 Signalosome Complex
  • DNA-Binding Proteins / metabolism*
  • Drosophila / metabolism*
  • Drosophila Proteins / metabolism*
  • Hedgehog Proteins / metabolism*
  • Image Processing, Computer-Assisted
  • Microscopy, Confocal
  • Multiprotein Complexes / metabolism*
  • NEDD8 Protein
  • Peptide Hydrolases / metabolism*
  • Phosphorylation
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Signal Transduction / physiology*
  • Transcription Factors / metabolism*
  • Ubiquitins / metabolism*
  • Wings, Animal / growth & development
  • Wings, Animal / metabolism

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Hedgehog Proteins
  • Multiprotein Complexes
  • NEDD8 Protein
  • Nedd8 protein, Drosophila
  • Transcription Factors
  • Ubiquitins
  • ci protein, Drosophila
  • dpp protein, Drosophila
  • hh protein, Drosophila
  • SKP Cullin F-Box Protein Ligases
  • Peptide Hydrolases
  • COP9 Signalosome Complex