title: Diverse polyubiquitin chains accumulate following 26S proteasomal dysfunction in mammalian neurones.
abstract: A generality has been that polyubiquitin chain linkage can differentially address proteins for various physiological processes. 26S proteasomal degradation is the most established function of ubiquitin signalling, classically linked to Lys48 polyubiquitin chains. The other well-characterised polyubiquitin linkage, via Lys63, mediates nonproteolytic functions. However, there are five other lysine residues and ubiquitin's amino terminus which can participate in polyubiquitination. Our 26S proteasome knockout mouse provides a unique opportunity to comprehensively investigate the ubiquitin signals in their physiological context in neurones following genetic inhibition of the proteasome, using quantitative mass spectrometry of ubiquitin linkage-specific signature peptides. We provide the first evidence for diverse polyubiquitin chains in mammalian neurones in vivo and show that polyubiquitin linked via Lys6, Lys11, Lys29 and Lys48, but not Lys63, accumulates upon 26S proteasome dysfunction. This adaptable nature of ubiquitin signals for proteasomal targeting could reflect the extensive cellular processes which are regulated by proteasome proteolysis and/or may involve specific ubiquitin linkage preferences for subsets of proteins in mammalian neurones. Our molecular pathological findings make a significant contribution to the understanding of ubiquitin signalling in ubiquitin-proteasome function.
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom. mbzlb@exmail.nottingham.ac.uk
authors.forename: Lynn
authors.initials: L
authors.lastname: Bedford
authors.forename: Robert
authors.initials: R
authors.lastname: Layfield
authors.forename: R John
authors.initials: RJ
authors.lastname: Mayer
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D008239:Lysine / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D017433:Protein Structure, Secondary; D015398:Signal Transduction / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology
chemical_list: D010455:Peptides; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D008239:Lysine