Direct evidence of importance of lysosomes in degradation of intracellular proteins

THE mechanisms of breakdown of intracellular proteins are largely unknown. It is widely presumed that lysosomes are important agents of this process ¹, chiefly because they contain suitable enzymes². Although autophagic uptake and degradation of cytoplasmic organelles by lysosomes has been described¹, there is only circumstantial evidence for significant lysosomal involvement in turnover of intracellular proteins ^3-6. Indeed, it is difficult to explain the heterogeneous turnover rates of proteins⁷ by a process involving bulk uptake of material¹. Furthermore, there is evidence for alternate systems of intracellular protein breakdown^5,8. In contrast, it has been shown that macrophage lysosomes are largely responsible for the degradation of endocytosed proteins, and that cathepsin D participates⁹. In the work reported here, breakdown of endogenous proteins of the perfused rat liver has been retarded by a specific inhibitor of cathepsin D, directed to the lysosomes, thus demonstrating their importance in the process.