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.
Highlights
Conjugation and deconjugation of target proteins with ubiquitin (Ub) and related proteins is an important posttranslational regulatory principle to control the stability, activity or location of modified substrates
We describe here a novel, conserved interplay between two physically interacting deneddylases that are specific for Nedd8
Defects in the A. nidulans COP9 signalosome deneddylase result in mutant strains which are unresponsive to light and blocked in sexual development [14,25]
Summary
Conjugation and deconjugation of target proteins with ubiquitin (Ub) and related proteins is an important posttranslational regulatory principle to control the stability, activity or location of modified substrates. Covalent attachment of Ubls as Nedd requires processing of a precursor peptide resulting in a free di-glycine motif at the C-terminus. All Ubls require in addition an ATP dependent activation cascade of an activating E1, a conjugating E2 enzyme and a substrate specific E3 ligase. Covalent attachment of Nedd is termed neddylation, whereas deneddylation is the reverse deconjugation reaction [2]. The major neddylation targets are the cullins which are scaffold proteins within the Cullin-RING ligases (CRL) which serve as ubiquitin ligases. Studies in mammalian cells showed that the Ub E3 CRL-RING component Rbx interacts with the Nedd E2 enzyme Ubc and acts as a Nedd E3 ligase for cullins [5]. The CUL1 containing CRLs have more than 350 substrates which include a number of factors involved in human tumor formation [7]
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