The inhibition of autophagy results in the inactivation of UPS. Autophagy inhibition causes the accumulation of the p62 complex, including protein aggregates, resulting in the delayed transport of ubiquitinated protein substrates to proteasomes. Moreover, the abnormal protein aggregates with p62 can inactivate the multiple regulators of the UPS, such as p97/VCP. The p62-aggregates also contained inactive components of the 26S proteasome complex as well as ubiquitinated proteins and the autophagosome. Accumulation of those inactive proteasome components would suppress the removal of ubiquitinated target proteins through the UPS. Thus, the inhibition of autophagy consequently reduces the proteasome degradation of ubiquitinated targets through various p62-regulated pathways.
