Mechanism and control of protein and RNA degradation in the rat hepatocyte: two modes of autophagic sequestration.

The control of protein and RNA degradation by amino acids, insulin, and glucagon was investigated in perfused livers from normal fed rats. Rates of breakdown were determined from the release of valine and cytidine after isotopic labelling in vivo. Stringent amino acid deprivation induced comparable increases (approximately 3.2% h-1) in the degradation of both macromolecular classes, and insulin inhibited them equally. By contrast, glucagon evoked the same proteolytic response at normal plasma concentrations but failed to stimulate RNA breakdown significantly. These and associated electron microscopic findings indicate the existence of two concentration-dependent modes of macroautophagy, one which sequesters both RNA and protein at low amino acid levels and a second which selectively takes up protein at normal concentrations. Control of macroautophagy is accomplished by seven regulatory amino acids and the permissive action of alanine. Alanine is required for effective inhibition by the regulatory group at normal concentrations; in its absence protein degradation accelerates sharply. This response, like that following the administration of glucagon, is mediated by the second mode.