title: Ubiquitin-protein conjugates: clinical and experimental findings.
abstract: Ubiquitin has been extensively studied as a protein which is a cofactor in extralysosomal protein degradation, particularly in reticulocyte lysates. Ubiquitin is also found conjugated to nuclear histones and surface receptors in somatic cells. Until recently the occurrence of stable cellular ubiquitin-protein conjugates in physiological and pathological states had not been considered and studied. Recently we have shown that ubiquitin-protein conjugate immunoreactivity is a clinical feature in several ostensibly unrelated chronic human degenerative diseases as well as in some viral diseases. The consistent observation is the occurrence of intracellular extralysosomal inclusions containing intermediate filaments and ubiquitin conjugates as determined by immunohistochemical methods. These diseases are therefore part of a family of intermediate filament-ubiquitin diseases. The involvement of intermediate filaments with ubiquitin, a protein of known significance in protein degradation, ties in with separate evidence for a close role between intermediate filaments and protein degradation. We have previously shown that intermediate filaments may be involved in protein sequestration for degradation in the lysosomal system. Clinical immunohistochemical observations suggest that elements of the lysosomal degradation system and the ubiquitin-dependent extralysosomal system are involved in the molecular pathogenesis of some diseases. To underpin these clinical observations, we have recently shown that ubiquitin-protein conjugates accumulate in lysosome-related multivesicular bodies in cells in which lysosomal degradation is impaired. This phenomenon may result from increased ubiquitin protein-conjugate formation in cells with a compromised lysosomal system followed by chance uptake into multivesicular bodies. Alternatively, ubiquitination may normally serve as a signal for protein uptake into the lysosomal system, ubiquitinated protein-conjugates may therefore accumulate in cells with a functionally impaired lysosomal system.
authors.affiliation: Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, UK.
authors.forename: F J
authors.initials: FJ
authors.lastname: Doherty
authors.forename: L
authors.initials: L
authors.lastname: Laszlo
authors.forename: J
authors.initials: J
authors.lastname: Lowe
authors.forename: G
authors.initials: G
authors.lastname: Lennox
authors.forename: M
authors.initials: M
authors.lastname: Landon
authors.forename: R J
authors.initials: RJ
authors.lastname: Mayer
mesh_terms: D002451:Cell Compartmentation; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D007382:Intermediate Filaments / Q000502:physiology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D008661:Metabolism, Inborn Errors / Q000378:metabolism; D015388:Organelles / Q000648:ultrastructure; D011506:Proteins / Q000378:metabolism*; D014452:Ubiquitins / Q000502:physiology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D011506:Proteins; D014452:Ubiquitins; D007930:Leucine; C024974:E 64