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The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors

Abstract

The rapamycin-sensitive TOR signalling pathway in Saccharomyces cerevisiae activates a cell-growth program in response to nutrients such as nitrogen and carbon1,2,3,4. The TOR1 and TOR2 kinases (TOR) control cytoplasmic protein synthesis and degradation through the conserved TAP42 protein5,6,7,8. Upon phosphorylation by TOR, TAP42 binds and possibly inhibits type 2A and type-2A-related phosphatases6,7,8; however, the mechanism by which TOR controls nuclear events such as global repression of starvation-specific transcription is unknown. Here we show that TOR prevents transcription of genes expressed upon nitrogen limitation by promoting the association of the GATA transcription factor GLN3 with the cytoplasmic protein URE2. The binding of GLN3 to URE2 requires TOR-dependent phosphorylation of GLN3. Phosphorylation and cytoplasmic retention of GLN3 are also dependent on the TOR effector TAP42, and are antagonized by the type-2A-related phosphatase SIT4. TOR inhibits expression of carbon-source-regulated genes by stimulating the binding of the transcriptional activators MSN2 and MSN4 to the cytoplasmic 14-3-3 protein BMH2. Thus, the TOR signalling pathway broadly controls nutrient metabolism by sequestering several transcription factors in the cytoplasm.

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Figure 1: TOR inhibits the GATA transcription factors GLN3 and GAT1.
Figure 2: GLN3 localization is controlled by TOR, URE2, TAP42 and SIT4.
Figure 3: GLN3 and URE2 form a phosphorylation-dependent, rapamycin-sensitive complex.
Figure 4: TOR promotes cytoplasmic retention of MSN and the BMH2–MSN interaction.
Figure 5: TOR promotes a cytoplasmic GLN3–URE2 complex via TAP42-mediated inhibition of the phosphatase SIT4, and thereby prevents nuclear accumulation of GLN3, in response to nutrients (nitrogen).

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Acknowledgements

We thank T. W. Sturgill and T. Schmelzle for comments on the manuscript, E. Jacinto for unpublished results, and A. Löschmann for technical assistance. The work was supported by grants of the Swiss National Science Foundation and the Canton of Basel (M.N.H.).

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Correspondence to Michael N. Hall.

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Beck, T., Hall, M. The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402, 689–692 (1999). https://doi.org/10.1038/45287

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