Fig. 9. UBB⁺¹ properties shift from UPS substrate to inhibitor. (1) UBB⁺¹ mRNA and translation levels are constant throughout life (Fischer et al., 2003; Gerez et al., 2005). In non-diseased tissue, the 26S proteasome is capable of degrading all the translated UBB⁺¹ and accumulation of UBB⁺¹ is not present. (2) Owing to various causes such as disease or aging, the efficiency of proteasomal degradation can decrease, leading to a diminished degradation of UBB⁺¹. (3) The levels of translated UBB⁺¹ exceed the degradation capacity of the proteasome and surpass the accumulation threshold. Accumulated UBB⁺¹ now holds UPS inhibitory properties itself, which can aggravate the initial decrease in UPS activity.