Coordinate regulation of autophagy and the ubiquitin proteasome system by MTOR

Abstract

Proteins in eukaryotic cells are continually being degraded to amino acids either by the ubiquitin proteasome system (UPS) or by the autophagic-lysosomal pathway. The breakdown of proteins by these 2 degradative pathways involves totally different enzymes that function in distinct subcellular compartments. While most studies of the UPS have focused on the selective ubiquitination and breakdown of specific cell proteins, macroautophagy/autophagy is a more global nonselective process. Consequently, the UPS and autophagy were traditionally assumed to serve distinct physiological functions and to be regulated in quite different manners. However, recent findings indicate that protein breakdown by these 2 systems is coordinately regulated by important physiological stimuli. The activation of MTORC1 by nutrients and hormones rapidly suppresses proteolysis by both proteasomes and autophagy, which helps promote protein accumulation, whereas in nutrient-poor conditions, MTORC1 inactivation causes the simultaneous activation of these 2 degradative pathways to supply the deprived cells with a source of amino acids. Also this selective breakdown of key anabolic proteins by the UPS upon MTORC1 inhibition can help limit growth-related processes (e.g., cholesterol biosynthesis). Thus, the collaboration of these 2 degradative systems, together with the simultaneous control of protein translation by MTORC1, provide clear advantages to the organism in both growth and starvation conditions.

Keywords: MTOR; autophagy; proteasomes; ubiquitination.

Figure 1.

Summary of the multiple actions of MTORC1 that synergize to promote protein accumulation when nutrient supply and growth factors are high. Recent findings demonstrate the coordinate suppression of overall protein degradation by the ubiquitin-proteasome system as well as autophagy, which occur simultaneously with the enhancement of protein synthesis. Conversely, nutrient deprivation or MTOR inhibitors cause rapid increases in ubiquitination and overall proteolysis by these 2 systems as protein synthesis decreases.