title: CSN-mediated deneddylation differentially modulates Ci(155) proteolysis to promote Hedgehog signalling responses.
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.
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: June-Tai
authors.initials: JT
authors.lastname: Wu
authors.forename: Wei-Hsiang
authors.initials: WH
authors.lastname: Lin
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Chen
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Huang
authors.forename: Chiou-Yang
authors.initials: CY
authors.lastname: Tang
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Ho
authors.forename: Haiwei
authors.initials: H
authors.lastname: Pi
authors.forename: Cheng-Ting
authors.initials: CT
authors.lastname: Chien
mesh_terms: D000818:Animals; D000075686:COP9 Signalosome Complex; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D018613:Microscopy, Confocal; D046912:Multiprotein Complexes / Q000378:metabolism*; D000075687:NEDD8 Protein; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C513173:Nedd8 protein, Drosophila; D014157:Transcription Factors; D014452:Ubiquitins; C092937:ci protein, Drosophila; C064196:dpp protein, Drosophila; C077245:hh protein, Drosophila; D044843:SKP Cullin F-Box Protein Ligases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex