CSN-mediated deneddylation differentially modulates Ci155 proteolysis to promote Hedgehog signalling responses

June-Tai Wu, Wei-Hsiang Lin, Wei-Yu Chen, Yi-Chun Huang, Chiou-Yang Tang, Margaret S. Ho, Haiwei Pi and Cheng-Ting Chien ()
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June-Tai Wu: Institute of Molecular Medicine, College of Medicine, National Taiwan University
Wei-Hsiang Lin: Institute of Molecular Biology, Academia Sinica
Wei-Yu Chen: Institute of Molecular Medicine, College of Medicine, National Taiwan University
Yi-Chun Huang: Chang-Gung University
Chiou-Yang Tang: Institute of Molecular Biology, Academia Sinica
Margaret S. Ho: Institute of Molecular Biology, Academia Sinica
Haiwei Pi: Chang-Gung University
Cheng-Ting Chien: Institute of Molecular Medicine, College of Medicine, National Taiwan University

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: 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 SCFSlimb-dependent ubiquitylation and proteolysis of Ci. How graded Hh signalling confers differential SCFSlimb-mediated Ci proteolysis in responding cells remains unclear. Here, we show that in COP9 signalosome (CSN) mutants, in which deneddylation of SCFSlimb 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.

Date: 2011
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DOI: 10.1038/ncomms1185

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