Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation.
Loss of neurons in neurodegenerative diseases is usually preceded by the accumulation of protein deposits that contain components of the ubiquitin/proteasome system. Affected neurons in Alzheimer's disease often accumulate UBB(+1), a mutant ubiquitin carrying a 19-amino acid C-terminal extension generated by a transcriptional dinucleotide deletion. Here we show that UBB(+1) is a potent inhibitor of ubiquitin-dependent proteolysis in neuronal cells, and that this inhibitory activity correlates with induction of cell cycle arrest. Surprisingly, UBB(+1) is recognized as a ubiquitin fusion degradation (UFD) proteasome substrate and ubiquitinated at Lys29 and Lys48. Full blockade of proteolysis requires both ubiquitination sites. Moreover, the inhibitory effect was enhanced by the introduction of multiple UFD signals. Our findings suggest that the inhibitory activity of UBB(+1) may be an important determinant of neurotoxicity and contribute to an environment that favors the accumulation of misfolded proteins.
Lindsten
Kristina
K
Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden.
de Vrij
Femke M S
FM
Verhoef
Lisette G G C
LG
Fischer
David F
DF
van Leeuwen
Fred W
FW
Hol
Elly M
EM
Masucci
Maria G
MG
Dantuma
Nico P
NP
D002453:Cell Cycle; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D008239:Lysine / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D008164:Luminescent Proteins; D009097:Multienzyme Complexes; D011506:Proteins; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine