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.

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy

“…Our study is consistent with emerging models of coordinated regulation of anabolic and catabolic aspects of proteostasis by the mTOR pathway and enables a potential framework for understanding how circadian clock control may integrate with nutrient signaling through BMAL1 proteostasis(Zhao and Goldberg, 2016). We do not yet understand how mTOR signaling regulates the ubiquitination of BMAL1.…”

Limited and digestive proteolysis: crosstalk between evolutionary conserved pathways

“…Ub-proteasomes are encapsulated by the autophagosome, which is targeted to the vacuole for degradation. (Zhao & Goldberg, 2016). This task-sharing points to the existence of common regulators and 'rules' that assure their coordinated and nonredundant functioning.…”

Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes

“…mTORC1 inhibition leads to the sequestration of these amino acids in the lysosome by slowing their movement across the lysosomal membrane, in effect converting it into a storage compartment for them. We speculate that this function of mTORC1 is important for preventing the inappropriate use of essential amino acids during amino acid starvation, a state in which lysosomal and proteasomal protein degradation are thought to be a major source of amino acids (30, 33, 34). One can imagine the following scenario: early in a starvation period mTORC1 becomes profoundly inhibited, which, by suppressing SLC38A9 and perhaps other transporters, prevents the exit from lysosomes of essential amino acids.…”