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.

The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient sensitive protein kinase that is aberrantly activated in many human cancers. However, whether dysregulation of mTORC1 signaling in normal tissues contributes to cancer risk is unknown. Here, we focused on hepatocellular carcinoma because it is a cancer with clear links to environmental factors that affect mTORC1, including dietary influences. Genetic ablation of the mTORC1 inhibitory component Tsc1 results in constitutively elevated mTORC1 signaling, an effect similar to that of obesity on this pathway. We found that mice with liver-specific knockout of Tsc1 developed sporadic hepatocellular carcinoma with heterogeneous histological and biochemical features. The spontaneous development of hepatocellular carcinoma in this mouse model was preceded by a series of pathological changes known to accompany the primary etiologies of this cancer, including liver damage, inflammation, necrosis, and regeneration. Chronic mTORC1 signaling caused unresolved endoplasmic reticulum stress and defects in autophagy, which contributed to hepatocyte damage and hepatocellular carcinoma development. Therefore, we demonstrate a previously unrecognized role for mTORC1 in carcinogenesis, perhaps representing a key molecular link between cancer risk and environmental factors, such as diet.

Parkinson’s disease is characterized by progressive death of dopaminergic neurons, leading to motor and cognitive dysfunction. Epidemiological studies consistently show that the use of tobacco reduces the risk of Parkinson’s. We report that nicotine reduces the abundance of SIRT6 in neuronal culture and brain tissue. We find that reduction of SIRT6 is partly responsible for neuroprotection afforded by nicotine. Additionally, SIRT6 abundance is greater in Parkinson’s patient brains, and decreased in the brains of tobacco users. We also identify SNPs that promote SIRT6 expression and simultaneously associate with an increased risk of Parkinson’s. Furthermore, brain-specific SIRT6 knockout mice are protected from MPTP-induced Parkinson’s, while SIRT6 overexpressing mice develop more severe pathology. Our data suggest that SIRT6 plays a pathogenic and pro-inflammatory role in Parkinson’s and that nicotine can provide neuroprotection by accelerating its degradation. Inhibition of SIRT6 may be a promising strategy to ameliorate Parkinson’s and neurodegeneration.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0625-y) contains supplementary material, which is available to authorized users.

Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson’s disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.