Ubiquitin-independent degradation of proteins by the proteasome.
The proteasome is the main proteolytic machinery of the cell and constitutes a recognized drugable target, in particular for treating cancer. It is involved in the elimination of misfolded, altered or aged proteins as well as in the generation of antigenic peptides presented by MHC class I molecules. It is also responsible for the proteolytic maturation of diverse polypeptide precursors and for the spatial and temporal regulation of the degradation of many key cell regulators whose destruction is necessary for progression through essential processes, such as cell division, differentiation and, more generally, adaptation to environmental signals. It is generally believed that proteins must undergo prior modification by polyubiquitin chains to be addressed to, and recognized by, the proteasome. In reality, however, there is accumulating evidence that ubiquitin-independent proteasomal degradation may have been largely underestimated. In particular, a number of proto-oncoproteins and oncosuppressive proteins are privileged ubiquitin-independent proteasomal substrates, the altered degradation of which may have tumorigenic consequences. The identification of ubiquitin-independent mechanisms for proteasomal degradation also poses the paramount question of the multiplicity of catabolic pathways targeting each protein substrate. As this may help design novel therapeutic strategies, the underlying mechanisms are critically reviewed here.
Jariel-Encontre
Isabelle
I
Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, IFR122, 1919 Route de Mende, Montpellier, F-34293, France.
Bossis
Guillaume
G
Piechaczyk
Marc
M
D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008954:Models, Biological; D009955:Ornithine Decarboxylase / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D000099169:Fos-Related Antigen 1
D050759:Cyclin-Dependent Kinase Inhibitor p21; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009955:Ornithine Decarboxylase; D046988:Proteasome Endopeptidase Complex; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D013940:Thymidylate Synthase; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D000099169:Fos-Related Antigen 1; C493956:CDKN1A protein, human; C497442:HIF1A protein, human