RRC ID 15564
Author Du J, Zhang J, Su Y, Liu M, Ospina JK, Yang S, Zhu AJ.
Title In vivo RNAi screen reveals neddylation genes as novel regulators of Hedgehog signaling.
Journal PLoS One
Abstract Hedgehog (Hh) signaling is highly conserved in all metazoan animals and plays critical roles in many developmental processes. Dysregulation of the Hh signaling cascade has been implicated in many diseases, including cancer. Although key components of the Hh pathway have been identified, significant gaps remain in our understanding of the regulation of individual Hh signaling molecules. Here, we report the identification of novel regulators of the Hh pathway, obtained from an in vivo RNA interference (RNAi) screen in Drosophila. By selectively targeting critical genes functioning in post-translational modification systems utilizing ubiquitin (Ub) and Ub-like proteins, we identify two novel genes (dUba3 and dUbc12) that negatively regulate Hh signaling activity. We provide in vivo and in vitro evidence illustrating that dUba3 and dUbc12 are essential components of the neddylation pathway; they function in an enzyme cascade to conjugate the ubiquitin-like NEDD8 modifier to Cullin proteins. Neddylation activates the Cullin-containing ubiquitin ligase complex, which in turn promotes the degradation of Cubitus interruptus (Ci), the downstream transcription factor of the Hh pathway. Our study reveals a conserved molecular mechanism of the neddylation pathway in Drosophila and sheds light on the complex post-translational regulations in Hh signaling.
Volume 6(9)
Pages e24168
Published 2011-9-8
DOI 10.1371/journal.pone.0024168
PII PONE-D-11-07360
PMID 21931660
PMC PMC3169580
MeSH Amino Acid Sequence Animals Cells, Cultured DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Drosophila Proteins / genetics* Drosophila Proteins / metabolism Drosophila melanogaster / genetics* Drosophila melanogaster / growth & development Drosophila melanogaster / metabolism Gene Expression Regulation, Developmental Hedgehog Proteins / genetics* Hedgehog Proteins / metabolism Immunoblotting In Situ Hybridization Larva / genetics Larva / growth & development Molecular Sequence Data Proteasome Endopeptidase Complex / metabolism RNA Interference* Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Amino Acid Signal Transduction* Transcription Factors / genetics Transcription Factors / metabolism Ubiquitin-Activating Enzymes / genetics Ubiquitin-Activating Enzymes / metabolism Ubiquitin-Conjugating Enzymes / genetics Ubiquitin-Conjugating Enzymes / metabolism Ubiquitination / genetics Wings, Animal / cytology Wings, Animal / growth & development Wings, Animal / metabolism
IF 2.74
Times Cited 11
Drosophila 1782R-2 7528R-1 7528R-2 15437R-1 11734R-1 11734R-3 17735R-2 3099R-2 3099R-3 3356R-1 4244R-1 4244R-2 4943R-1 4943R-2 5087R-2 5087R-3 6190R-1 6190R-3 7555R-1 8184R-1 8184R-6 11414R-3 9484R-1 9484R-2 11534R-1 10981R-3 11534R-3 10981R-4 11988R-1 11321R-3 11988R-3 1134R-2 12200R-1 11360R-2 12200R-3 11360R-4 12284R-2 12362R-1 11414R-1 12362R-3 12489R-1 13025R-1 13025R-2 13030R-2 13030R-3 13344R-1 13835R-2 13835R-4 14435R-1 14435R-4 15011R-3 15104R-2 15104R-3 15150R-1 17019R-3 17019R-6 17033R-2 17033R-3 17260R-1 17260R-2 17492R-1 17492R-3 1815R-1 2304R-2 2304R-3 2617R-1 2679R-3 2681R-2 2682R-1 2709R-2 2709R-3 2926R-2 31053R-1 31053R-3 31716R-1 31716R-2 31807R-2 31807R-3 9268R-1 9268R-3 3231R-1 3639R-1 3886R-1 3929R-1 3929R-2 4195R-1 4195R-4 4813R-1 4813R-3 4909R-1 4909R-3 4973R-1 4973R-4 5071R-1 5071R-2 5334R-1 5334R-3 5347R-1 5347R-3 5709R-1 6688R-3 6752R-1 7037R-1 7037R-2 7081R-2 7694R-1 7694R-2 8293R-1 8293R-2 8786R-1 8786R-4 8910R-1 8910R-3 8974R-2 9014R-1 9014R-2 9086R-3 9576R-1 9576R-3 9949R-1 9949R-2 11861R-1 11861R-2 1401R-1 1401R-2 1512R-1 1512R-3 1877R-1 1877R-2 3060R-2 8711R-2 11044R-1 11044R-2 12765R-1 12765R-3 15010R-2 15010R-3 15437R-1 2010R-1 31633R-2 32085R-1 3412R-1 3412R-3 3428R-1 3428R-3 4911R-1 5003R-1 5003R-3 5961R-1 7148R-1 7148R-2 7707R-1 8272R-1 8272R-2 9144R-1 9144R-2 9316R-1 9952R-1 9952R-2 11941R-3 11942R-3 12227R-1 12227R-2 12700R-2 16983R-3 8881R-4 2218R-2 2218R-4 5203R-2 5203R-3 5519R-1 14472R-1 14472R-3 15141R-1 15141R-4