The role of Lys-63 ubiquitin chains in targeting proteins for proteasomal degradation is still obscure. We systematically compared proteasomal processing of Lys-63 ubiquitin chains with that of the canonical proteolytic signal, Lys-48 ubiquitin chains. Quantitative mass spectrometric analysis of ubiquitin chains in HeLa cells determines that the levels of Lys-63 ubiquitin chains are insensitive to short-time proteasome inhibition. Also, the Lys-48/Lys-63 ratio in the 26 S proteasome-bound fraction is 1.7-fold more than that in the cell lysates, likely because some cellular Lys-63 ubiquitin conjugates are sequestered by Lys-63 chain-specific binding proteins. In vitro, Lys-48 and Lys-63 ubiquitin chains bind the 26 S proteasome comparably, whereas Lys-63 chains are deubiquitinated 6-fold faster than Lys-48 chains. Also, Lys-63 tetraubiquitin-conjugated UbcH10 is rapidly deubiquitinated into the monoubiquitinated form, whereas Lys-48 tetraubiquitin targets UbcH10 for degradation. Furthermore, we found that both the ubiquitin aldehyde- and 1,10-phenanthroline-sensitive deubiquitinating activities of the 26 S proteasome contribute to Lys-48- and Lys-63-linkage deubiquitination, albeit the inhibitory extents are different. Together, our findings suggest that compared with Lys-48 chains, cellular Lys-63 chains have less proteasomal accessibility, and proteasome-bound Lys-63 chains are more rapidly deubiquitinated, which could cause inefficient degradation of Lys-63 conjugates.
"In contrast to POH1, USP14 and UCHL5 share a different mode of action and preferentially cleave ubiquitin from the distal ends of ubiquitin chains leading to progressive chain shortening the recycling of ubiquitin back into the UPS. USP14 preferentially cleaves Lys48-linked polyubiquitin chains (Hanna et al., 2006; Hu et al., 2005), whereas UCHL5 appears to be more promiscuous, cleaving both Lys48-and Lys63-linkage types (Jacobson et al., 2009). Interestingly, USP14 appears to hinder proteasome degradation by actively trimming ubiquitin chains on target proteins resulting in prolonged occupancy at the 19S RP and potentially favouring release back to the cytosol (Hanna et al., 2006; Lee et al., 2010, 2011b). "
"E3 function regulates protein degradation, Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/developmentalbiology apoptosis, signaling, protein trafficking, and transcription (Hershko and Ciechanover, 1998; Jacobson et al., 2009; Komander, 2009). E3 ubiquitin ligases are grouped into two major classes: HECT (Homologous to the E6-AP Carboxyl Terminus)-domain and RING (Really Interesting New Gene)-finger E3 ligases (Ardley and Robinson , 2005; Kipreos, 2005; Metzger et al., 2012). "
"Although all possible linkage types are present in cells, their precise functions remain only partially understood (Xu et al., 2009). Chains formed through the addition of ubiquitin exclusively at lysine 48 (K48) have been recognized to signal protein degradation (Glickman and Ciechanover, 2002), whereas K63-linked ubiquitin chains seem to subserve diverse functions beyond protein degradation (Jacobson et al., 2009). For example, K63-linked chains regulate NF-κB signaling not by promoting protein degradation but by influencing ubiquitin-dependent protein-protein interactions (Hadian et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Control of proper protein synthesis, function, and turnover is essential for the health of all cells. In neurons these demands take on the additional importance of supporting and regulating the highly dynamic connections between neurons that are necessary for cognitive function, learning, and memory. Regulating multiple unique synaptic protein environments within a single neuron while maintaining cell health requires the highly regulated processes of ubiquitination and degradation of ubiquitinated proteins through the proteasome. In this review, we examine the effects of dysregulated ubiquitination and protein clearance on the handling of disease-associated proteins and neuronal health in the most common neurodegenerative diseases.
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