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Prolyl isomerase Pin1 acts as a switch to control the degree of substrate ubiquitylation

Nature Cell Biology volume 11, pages 967972 (2009) | Download Citation

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Abstract

Pin1, a conserved eukaryotic peptidyl-prolyl cis/trans isomerase, has important roles in cellular regulation1,2. Because of its activity to switch the conformation of peptidyl-proline bonds in polypeptide chains, Pin1 operates as a binary switch, often in fate-determining pathways. Pin1 activity is usually controlled by substrate phosphorylation1,2, but how Pin1 switches protein fates has been unclear. Here we show that Pin1 controls the degree of substrate ubiquitylation and thereby protein functions. We found that yeast Pin1 (Ess1) is essential for viability because it controls the NF-κB-related Spt23 transcription factor involved in unsaturated fatty-acid synthesis3. High Pin1 activity results in low ubiquitylation of Spt23, which triggers Spt23 precursor processing and hence transcription factor activation. By contrast, decreased Pin1 activity leads to robust Spt23 polyubiquitylation and subsequent proteasomal degradation. Inhibition of Pin1 in mammalian cells changes the ubiquitylation status of the tumour suppressor protein p53 from oligoubiquitylation, which is known to trigger nuclear export4, to polyubiquitylation, which causes nuclear p53 degradation. This suggests that the Pin1 activity is often translated into a fate-determining ubiquitylation switch, and that Pin1 may affect the degree of substrate ubiquitylation in other pathways as well.

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Acknowledgements

We thank T. Ammon, A. Buchberger, M. Kalocsay, S. Müller, W. Piwko and C. Pohl for discussions, and M. Kalocsay for the pOLE1 reporter construct. S.J. is supported by the Max Planck Society, the Center for Integrated Protein Science Munich, the RUBICON EU Network of Excellence, and Fonds der Chemischen Industrie.

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Affiliations

  1. Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.

    • Dirk Siepe
    •  & Stefan Jentsch

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Contributions

D.S. conducted the experiments. D.S. and S.J. conceived the experiments, discussed the results and prepared the manuscript.

Corresponding author

Correspondence to Stefan Jentsch.

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https://doi.org/10.1038/ncb1908

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