Intracellular protein degradation: basis of a self-regulating mechanism for the proteolysis of endogenous proteins.

The intracellular basal proteolysis system, as distinct from the lysosomal system, is important in sustaining a high flux of proteins required for maintenance, growth and adaptability of cells. Its activity automatically fluctuates with changes in protein synthetic activity, but with a considerably slower response time, since the two processes are only indirectly or passively linked. Since as much as one-third of intracellular proteolysis in mammalian cells is directed as nascent proteins, the consequences are more fully discussed in relation to cell growth state. During rapid growth, cells have to accumulate more than double their original protein mass in order to achieve a 100% increase between divisions. The effects of reducing protein synthesis by inducing quiescence, serum step-down or cycloheximide treatment on intracellular proteolysis are considered, and the possibility that this leads to enhanced degradation of existing proteins has been explored. No substantial evidence was found to support this latter notion. The basal proteolysis system is seen as a constitutive, pervasive and broad-spectrumed collection of hydrolytic enzymes. It destroys proteins randomly, having no means of distinguishing young from old, aberrant from normal. The rate of demise of protein substrates depends on two factors, the ease of access of the hydrolytic enzymes to their peptide bonds, and the length of time that any species of protein remains at risk to this hydrolytic potential. While the former has long been recognized, the importance of the second factor in relation to the ability of proteins to become integrated in the living fabric of the cell is only beginning to be appreciated. The discussion also suggests elaborate regulatory mechanisms akin to those for protein synthesis would be unnecessary for protein degradation, especially if it can now be substantiated that substrate availability determines the turnover rates of proteins by a pervasive and relatively unlimited proteolytic system (Grisolía, 1964).