Abstract
Ubiquitin is a highly conserved 76 amino acid polypeptide, which is covalently attached to target proteins to signal their degradation by the 26S proteasome or to modify their function or localization. Regulated protein degradation, which is associated with many dynamic cellular processes, occurs predominantly via the ubiquitin-proteasome system. Ubiquitin is conjugated to target proteins through the sequential actions of a ubiquitin-activating enzyme, ubiquitin-conjugating enzymes, and ubiquitin-protein ligases. The nematode Caenorhabditis elegans has one ubiquitin-activating enzyme, twenty putative ubiquitin-conjugating enzymes, and potentially hundreds of ubiquitin-protein ligases. Research in C. elegans has focused on the cellular functions of ubiquitin pathway components in the context of organismal development. A combination of forward genetics, reverse genetics, and genome-wide RNAi screens has provided information on the loss-of-function phenotypes for the majority of C. elegans ubiquitin pathway components. Additionally, detailed analysis of several classes of ubiquitin-protein ligases has led to the identification of their substrates and the molecular pathways that they regulate. This review presents a comprehensive overview of ubiquitin-mediated pathways in C. elegans with a description of the known components and their identified molecular, cellular, and developmental functions.
Highlights
Ubiquitin-mediated pathways in C. elegans comprehensive overview of ubiquitin-mediated pathways in C. elegans with a description of the known components and their identified molecular, cellular, and developmental functions
Mutations of the RING finger domain of RNF-5 severely reduce its ability to lower UNC-95 protein levels upon overexpression (Broday et al, 2004). These results suggest that RNF-5 directly targets UNC-95 for ubiquitin-mediated proteolysis
Co-expression of RPM-1 and DLK-1 in mammalian cells promotes the ubiquitination of DLK-1, and DLK-1 is co-immunoprecipitated by the C-terminus of RPM-1, suggesting that RPM-1 directly binds and mediates DLK-1 ubiquitination (Nakata et al, 2005). These results identified the first ubiquitinated substrate of an RPM-1 family member, which control synapse formation in Drosophila and mammals (Chang and Balice-Gordon, 2000; Burgess et al, 2004)
Summary
Ubiquitin (Ub) is a ubiquitously expressed and highly conserved 76 amino acid polypeptide (Hershko and Ciechanover, 1998; Figure 1A). The covalent tandem attachment of multiple Ub to a target protein to form poly-ubiquitin chains can mark the protein for degradation by the 26S proteasome. Poly-Ub chains created by conjugation through a Lys-48 linkage targets a substrate for degradation by the 26S proteasome. Poly-Ub formed by Lys-63 conjugation does not lead to proteasome-mediated degradation, but instead is associated with the regulation of endocytosis or changes in target. The 26S proteasome is a conserved chambered protease complex that is present in both the cytoplasm and the nucleus (Wojcik and DeMartino, 2003) It consists of a 20S proteasome, a central core containing proteolytic subunits, and two 19S regulatory complexes that bind to ubiquitinated substrates, cleave off ubiquitin, and unfold and translocate the substrate into the 20S core (Pickart and Cohen, 2004). RNAi depletion of proteasome components during larval stages produces larval arrest and lethality while RNAi depletion in adult hermaphrodites produces progeny that arrest at the one-cell stage with defective meiosis I, indicating the central importance of this pathway (Takahashi et al, 2002; Gonczy et al, 2000)
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