Coordinated regulation of protein synthesis and degradation by mTORC1

Abstract

Eukaryotic cells coordinately control anabolic and catabolic processes to maintain cell and tissue homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) promotes nutrient-consuming anabolic processes, such as protein synthesis1. Here, we show that accompanying an increase in protein synthesis, mTORC1 activation also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor nuclear factor erythroid-derived 2-related factor 1 (NFE2L1 or NRF1). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumor suppressors or physiological activation of mTORC1 in response to growth factors or feeding resulted in increased NRF1 expression in cells and tissues. We find that this NRF1-dependent elevation of proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. Therefore, mTORC1 signaling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis.

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

“…Alternatively, when available, the analysis of CNOT6 and CNOT6L +/− heterozygous mice would also shed some light on possible functions of CNOT in aging. On the other hand, it is also possible that changes in proteasomal function in slow‐aging mice could contribute to the elevation of MGMT, NDRG1, and CNOT6L (Wang & Miller, 2012; Zhang et al ., 2014; Zhang & Manning, 2015). …”

Coordinate regulation of autophagy and the ubiquitin proteasome system by MTOR

“…In fact, that study did not detect any protein breakdown for many hours after synthesis (when proteolysis is most rapid), nor the wellestablished enhancement of autophagy upon MTORC1 inhibition. 12 Moreover, this delayed reduction in the transcription of proteasomal components after MTOR inhibition is unlikely to reduce proteasome content or protein degradation within 5-16 h as proposed by Zhang et al because proteasomes have Figure 1. Summary of the multiple actions of MTORC1 that synergize to promote protein accumulation when nutrient supply and growth factors are high.…”

“…Surprisingly, a recent study actually reported the opposite conclusion: MTORC1 inhibition reduces proteasomal degradation by suppressing the expression of new proteasomes. 12 However, as we demonstrated elsewhere, 6,13 the methodology used in that study for measuring protein degradation and therefore their conclusions on proteolysis are questionable and potentially misleading. In fact, that study did not detect any protein breakdown for many hours after synthesis (when proteolysis is most rapid), nor the wellestablished enhancement of autophagy upon MTORC1 inhibition.…”

“…Therefore, changes in proteasome gene expression are unlikely to alter overall proteolysis rates upon changes in nutrient availability or during diurnal cycles as suggested recently. 12 When nutrients and growth factors are abundant for prolonged periods and MTORC1 activity is high, expression of new proteasomes and ribosomes may serve to enable cells to undergo cell division.…”

THE EFFECTS OF Jatropha curcas L SEED EXTRACT IN REGULATION EXPRESSION TUMOR MARKER OF TGF- β1 GENE

“…Regulasi sintesis protein dimaksud yaitu bila protein yang diperlukan akan dtranskripsikan dan sebaliknya bila tidak diperlukan produksi protein dihentikan. Walaupun terjadi peningkatan kadar mRNA, tidak seluruhnya disintesis menjadi protein (Zhang et al, 2014).…”