Abstract
mTORC1 activation promotes an increased capacity for protein degradation.
Major finding: mTORC1 activation promotes an increased capacity for protein degradation.
Mechanism: mTORC1 mediates increased expression of proteasome genes through induction of NRF1.
Impact: mTORC1-induced proteasome activity increases amino acid pools for sustained protein synthesis.
mTOR complex 1 (mTORC1) stimulates anabolic cellular processes such as protein synthesis in response to growth signals and is chronically activated in many human tumors. Zhang and colleagues investigated an additional role for mTORC1 activation in the maintenance of protein homeostasis. Cells lacking components of the tuberous sclerosis complex (TSC) protein complex, a negative regulator of mTORC1, exhibited increased rates of protein degradation that were reversed by treatment with the mTORC1 inhibitor rapamycin. This rapamycin-sensitive increase in protein turnover was maintained in the presence of lysosomal inhibitors and in autophagy-deficient cell lines, but was abrogated in the presence of proteasome inhibitors, suggesting that increased protein degradation following mTORC1 activation is mediated by the proteasome. Indeed, Tsc2-null cells exhibited higher proteasome activity and elevated cellular proteasome levels that were both reversed by mTORC1 inhibition. Further, mTORC1 activation was associated with increased transcription of genes encoding proteasome subunits. Knockdown of the transcription factor nuclear factor erythroid-derived 2-related factor 1 (NFE2L1, also known as NRF1), an established regulator of proteasome gene expression, blocked mTORC1-mediated induction of proteasome genes, whereas overexpression of NRF1 resulted in increased proteasome levels that were resistant to rapamycin, indicating that NRF1 functions downstream of mTORC1 in stimulating proteasome activity. mTORC1 activation induced the transcription of NRF1 via the transcription factor sterol regulatory element binding protein 1, which directly bound to the NRF1 promoter region. Importantly, genetic and physiologic mTORC1 activation in vivo in mouse brain and liver was associated with increased NRF1 and proteasome gene expression. Moreover, similar to the effects of proteasome inhibitor treatment, NRF1 depletion diminished intracellular amino acids and reduced the rate of protein synthesis. Together, these findings establish a role for mTORC1 signaling in the induction of proteasome-mediated protein degradation as a mechanism to maintain adequate amino acid pools to sustain an increased rate of protein synthesis.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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