Inhibition of hepatocytic protein degradation by inducers of autophagosome accumulation.

Out of nine compounds known to induce accumulation of autophagosomes, seven were found to inhibit degradation of endogenous protein and all of them to inhibit degradation of an exogenous protein (asialofetuin) in isolated rat hepatocytes. On the basis of these findings we propose two possible common mechanisms by which the drugs may cause autophagosome accumulation: 1) The inhibition of protein degradation may result in a decrease in the intracellular amino acid levels, a change which in turn serves as a stimulus for increased autophagic sequestration. 2) Disturbance of the function of the lysosomes may reduce their ability to fuse with newly formed autophagosomes, thereby causing accumulation of the latter.