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Ubiquitin–proteasome system (UPS) is the principal intracellular
pathway for selective degradation of short-lived, damaged, misfolded and regulatory
proteins. Proteins are tagged with ubiquitin through E1 activating enzymes, E2
conjugating enzymes and E3 ubiquitin ligases, after which many polyubiquitinated
substrates are degraded by the 26S proteasome. The UPS regulates protein quality
control, cell-cycle progression, apoptosis, DNA repair, transcription, inflammation
and stress responses. In established cancers, tumour cells may become highly dependent
on proteasome activity to remove abnormal proteins and maintain rapid proliferation;
therefore, proteasome inhibition can cause proteotoxic stress, cell-cycle arrest and
apoptosis. In Alzheimer’s disease and other neurodegenerative disorders, impaired or
overloaded UPS activity may reduce clearance of abnormal proteins and contribute to
amyloid-β and tau accumulation. Consequently, the desired modulation is
context-dependent: proteasome or UPS activity is commonly inhibited
for anticancer treatment, whereas restoration or enhancement of selective protein
clearance may be desirable in neurodegeneration.
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