Doherty F J, Laszlo L, Lowe J, Lennox G, Landon M, Mayer R J
Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, UK.
Revis Biol Celular. 1989;20:255-73.
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.
泛素作为一种在溶酶体外蛋白质降解中起辅助因子作用的蛋白质，尤其是在网织红细胞裂解物中，已经得到了广泛研究。在体细胞中也发现泛素与核组蛋白和表面受体结合。直到最近，才开始考虑和研究在生理和病理状态下稳定的细胞泛素-蛋白质结合物的存在情况。最近我们发现，泛素-蛋白质结合物免疫反应性是几种表面上不相关的慢性人类退行性疾病以及一些病毒疾病的临床特征。通过免疫组织化学方法确定，一致观察到的现象是细胞内溶酶体外包含中间丝和泛素结合物的包涵体的出现。因此，这些疾病属于中间丝-泛素疾病家族的一部分。中间丝与泛素（一种在蛋白质降解中具有已知重要性的蛋白质）的关联，与中间丝和蛋白质降解之间密切关系的其他证据相吻合。我们之前已经表明，中间丝可能参与了溶酶体系统中蛋白质的隔离以便降解。临床免疫组织化学观察表明，溶酶体降解系统和泛素依赖性溶酶体外系统的成分参与了某些疾病的分子发病机制。为了支持这些临床观察结果，我们最近发现，在溶酶体降解受损的细胞中，泛素-蛋白质结合物积聚在与溶酶体相关的多囊泡体中。这种现象可能是由于溶酶体系统受损的细胞中泛素-蛋白质结合物形成增加，随后偶然被多囊泡体摄取所致。或者，泛素化可能通常作为蛋白质进入溶酶体系统的信号，因此泛素化的蛋白质结合物可能在溶酶体系统功能受损的细胞中积聚。
