mTORC1 signaling activates NRF1 to increase cellular proteasome levels - PubMed (original) (raw)

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mTORC1 signaling activates NRF1 to increase cellular proteasome levels

Yinan Zhang et al. Cell Cycle. 2015.

Abstract

Defects in the maintenance of protein homeostasis, or proteostasis, has emerged as an underlying feature of a variety of human pathologies, including aging-related diseases. Proteostasis is achieved through the coordinated action of cellular systems overseeing amino acid availability, mRNA translation, protein folding, secretion, and degradation. The regulation of these distinct systems must be integrated at various points to attain a proper balance. In a recent study, we found that the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway, well known to enhance the protein synthesis capacity of cells while concordantly inhibiting autophagy, promotes the production of more proteasomes. Activation of mTORC1 genetically, through loss of the tuberous sclerosis complex (TSC) tumor suppressors, or physiologically, through growth factors or feeding, stimulates a transcriptional program involving the sterol-regulatory element binding protein 1 (SREBP1) and nuclear factor erythroid-derived 2-related factor 1 (NRF1; also known as NFE2L1) transcription factors leading to an increase in cellular proteasome content. As discussed here, our findings suggest that this increase in proteasome levels facilitates both the maintenance of proteostasis and the recovery of amino acids in the face of an increased protein load consequent to mTORC1 activation. We also consider the physiological and pathological implications of this unexpected new downstream branch of mTORC1 signaling.

Keywords: NFE2L1; NRF2; aging; cancer; muscle; neurodegeneration; proteasome; synaptic plasticity.

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Figures

Figure 1.

Figure 1.

The mTORC1-SREBP-NRF1-Proteasome pathway. Growth factors and nutrients activate mTORC1, which promotes an increase in cellular protein synthesis. mTORC1 also stimulates activation of the SREBP1 transcription factor by promoting its processing and nuclear accumulation, which requires its trafficking to the Golgi, where it is proteolytically cleaved by 2 proteases, resulting in release of the N-terminus encompassing the mature active transcription factor. Mature SREBP1 binds to SRE sequences in the promoters of genes, including the enzymes of de novo lipid synthesis and NFE2L1, encoding the NRF1 transcription factor. NRF1 is synthesized as an ER transmembrane protein and must be processed to release the active transcription factor. Proteasome inhibitors stimulate this processing, but the nature of the physiological signal is currently unknown. Once activated, NRF1 goes to the nucleus and turns on a subset of genes containing AREs in their promoter, including those encoding all, or nearly all, subunits of the proteasome, leading to an increase in cellular proteasome content. See text for more details.

Figure 2.

Figure 2.

The temporal response to mTORC1 activation. Within the first hour of mTORC1 activation, it stimulates the translation of 5′TOP mRNAs, inhibits autophagy, and promotes SREBP activation, initiating a cascade of cellular events that promote cell growth while protecting from proteotoxic stress. A key feature of this program is the delayed production of proteasomes by NRF1 induction, which enhances the efficiency of protein degradation following the global increase in protein synthesis, thereby facilitating the clearance of proteins and misfolded proteins that have been independently targeted for degradation by target-specific E3-ubiquitin (Ub) ligases. Downstream of SREBP transcriptional targets, the activation of lipid synthesis and expansion of cellular membranes combined with the NRF1-dependent increase in proteasomes and protein turnover protects cells with activated mTORC1 signaling from proteotoxic stress, including ER stress. The time scale on the top provides a rough estimate of the kinetics of this response, with the precise timing likely to vary in different cell and tissue settings. See text for more details.

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