Effects of mTORC1 inhibition on proteasome activity and levels
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The mechanistic target of rapamycin (mTOR) regulates numerousextracellular and intracellular signals involved in the maintenanceof cellular homeostasis and cell growth. mTOR also functionsas an endogenous inhibitor of autophagy. Under nutrient-rich conditions,mTOR complex 1 (mTORC1) phosphorylates the ULK1complex, preventing its activation and subsequent autophagosomeformation, while inhibition of mTORC1 using either rapamycinor nutrient deprivation induces autophagy. Autophagyand proteasomal proteolysis provide amino acids necessary forprotein translation. Although the connection between mTORC1and autophagy is well characterized, the association of mTORC1inhibition with proteasome biogenesis and activity has not beenfully elucidated yet. Proteasomes are long-lived cellular organelles. Their spatiotemporal rather than homeostatic regulation couldbe another adaptive cellular mechanism to respond to starvation. Here, we reviewed several published reports and the latest researchfrom our group to examine the connection between mTORC1and proteasome. We have also investigated and described theeffect of mTORC1 inhibition on proteasome activity using purifiedproteasomes. Since mTORC1 inhibitors are currently evaluatedas treatments for several human diseases, a better understandingof the link between mTORC1 activity and proteasome function isof utmost importance.
Abstract
The mechanistic target of rapamycin (mTOR) regulates numerousextracellular and intracellular signals involved in the maintenanceof cellular homeostasis and cell growth. mTOR also functionsas an endogenous inhibitor of autophagy. Under nutrient-rich conditions,mTOR complex 1 (mTORC1) phosphorylates the ULK1complex, preventing its activation and subsequent autophagosomeformation, while inhibition of mTORC1 using either rapamycinor nutrient deprivation induces autophagy. Autophagyand proteasomal proteolysis provide amino acids necessary forprotein translation. Although the connection between mTORC1and autophagy is well characterized, the association of mTORC1inhibition with proteasome biogenesis and activity has not beenfully elucidated yet. Proteasomes are long-lived cellular organelles. Their spatiotemporal rather than homeostatic regulation couldbe another adaptive cellular mechanism to respond to starvation. Here, we reviewed several published reports and the latest researchfrom our group to examine the connection between mTORC1and proteasome. We have also investigated and described theeffect of mTORC1 inhibition on proteasome activity using purifiedproteasomes. Since mTORC1 inhibitors are currently evaluatedas treatments for several human diseases, a better understandingof the link between mTORC1 activity and proteasome function isof utmost importance.
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