Control of multicellular development by the physically interacting deneddylases DEN1/DenA and COP9 signalosome

PLoS Genet. 2013;9(2):e1003275. doi: 10.1371/journal.pgen.1003275. Epub 2013 Feb 7.

Abstract

Deneddylases remove the ubiquitin-like protein Nedd8 from modified proteins. An increased deneddylase activity has been associated with various human cancers. In contrast, we show here that a mutant strain of the model fungus Aspergillus nidulans deficient in two deneddylases is viable but can only grow as a filament and is highly impaired for multicellular development. The DEN1/DenA and the COP9 signalosome (CSN) deneddylases physically interact in A. nidulans as well as in human cells, and CSN targets DEN1/DenA for protein degradation. Fungal development responds to light and requires both deneddylases for an appropriate light reaction. In contrast to CSN, which is necessary for sexual development, DEN1/DenA is required for asexual development. The CSN-DEN1/DenA interaction that affects DEN1/DenA protein levels presumably balances cellular deneddylase activity. A deneddylase disequilibrium impairs multicellular development and suggests that control of deneddylase activity is important for multicellular development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspergillus nidulans* / genetics
  • Aspergillus nidulans* / growth & development
  • COP9 Signalosome Complex
  • Endopeptidases* / genetics
  • Endopeptidases* / metabolism
  • Gene Expression Regulation, Fungal
  • HeLa Cells
  • Humans
  • Multiprotein Complexes* / genetics
  • Multiprotein Complexes* / metabolism
  • Mutation
  • NEDD8 Protein
  • Peptide Hydrolases* / genetics
  • Peptide Hydrolases* / metabolism
  • Protein Processing, Post-Translational
  • Proteolysis
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Ubiquitins* / genetics
  • Ubiquitins* / metabolism

Substances

  • Multiprotein Complexes
  • NEDD8 Protein
  • NEDD8 protein, human
  • Ubiquitins
  • Endopeptidases
  • Peptide Hydrolases
  • COP9 Signalosome Complex
  • SENP8 protein, human

Grants and funding

Funding for this work was received from the “Deutsche Forschungsgemeinschaft (DFG)” (http://www.dfg.de/), the DFG Priority Program SPP1365 (http://ubfnet.charite.de), the DFG SFB860 (http://msb.bio.uni-goettingen.de/SFB860/), and the ERA-NET PathoGenoMics project (http://www.pathogenomics-era.net/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.