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Plasma membrane stress induces relocalization of Slm proteins and activation of TORC2 to promote sphingolipid synthesis

Nature Cell Biology volume 14, pages 542–547 (2012)Cite this article

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Abstract

The plasma membrane delimits the cell, and its integrity is essential for cell survival. Lipids and proteins form domains of distinct composition within the plasma membrane. How changes in plasma membrane composition are perceived, and how the abundance of lipids in the plasma membrane is regulated to balance changing needs remains largely unknown. Here, we show that the Slm1/2 paralogues and the target of rapamycin kinase complex 2 (TORC2) play a central role in this regulation. Membrane stress, induced by either inhibition of sphingolipid metabolism or by mechanically stretching the plasma membrane, redistributes Slm proteins between distinct plasma membrane domains. This increases Slm protein association with and activation of TORC2, which is restricted to the domain known as the membrane compartment containing TORC2 (MCT; ref. 1). As TORC2 regulates sphingolipid metabolism2, our discoveries reveal a homeostasis mechanism in which TORC2 responds to plasma membrane stress to mediate compensatory changes in cellular lipid synthesis and hence modulates the composition of the plasma membrane. The components of this pathway and their involvement in signalling after membrane stretch are evolutionarily conserved.

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Figure 1: TORC2 activation following sphingolipid synthesis inhibition is dependent on Slm proteins.
Figure 2: Relocalization of Slm proteins in response to sphingolipid synthesis inhibition correlates with TORC2 activation.
Figure 3: Relocalization of Slm proteins away from eisosomes is required for TORC2 activation.
Figure 4: Slm proteins mediate TORC2 activation in response to membrane stretch.

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Acknowledgements

The authors are grateful to R. Wedlich-Söldner for helping with TIRF microscopy, to P. deCamilli, R. V. Farese Jr, T. Halazonetis, J. Paszkowski, M. Gonzalez-Gaitan and members of the Walther and Loewith laboratories for comments on the manuscript and to A. Huber, Y. Kamada, J. Urban, G. Tevzadze and S. Emr for the ypk1L424G, YPK2D239A, GTR1/gtr1S20L constructs and tor2W2469A, W2473A and slmts strains, respectively. T.C.W. acknowledges support from the German Research Council (DFG) and the Minna–James–Heineman Foundation. H.R. and A.R. acknowledge support from SystemsX.ch and the Human Frontier Science Program, respectively. R.L. acknowledges support from the National Centre for Competence in Research (NCCR) Frontiers in Genetics, and the European Research Council. H.R., A.R. and R.L. acknowledge support from the Swiss National Science Foundation, the NCCR Chemical Biology and the Canton of Geneva.

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Author notes

  1. Doris Berchtold and Manuele Piccolis: These authors contributed equally to this work

  2. Tobias C. Walther and Robbie Loewith: These authors contributed equally to this work

Authors and Affiliations

  1. Max Planck Institute of Biochemistry, Organelle Architecture and Dynamics, 82152 Martinsried, Germany

    Doris Berchtold & Tobias C. Walther

  2. Department of Molecular Biology, University of Geneva, Geneva 1211, Switzerland

    Manuele Piccolis & Robbie Loewith

  3. Department of Biochemistry, University of Geneva, Geneva 1211, Switzerland

    Nicolas Chiaruttini, Isabelle Riezman, Howard Riezman & Aurélien Roux

  4. Swiss National Centre for Competence in Research Programme Chemical Biology, Geneva 1211, Switzerland

    Howard Riezman, Aurélien Roux & Robbie Loewith

  5. Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    Tobias C. Walther

  6. Swiss National Centre for Competence in Research Programme Frontiers in Genetics, Geneva 1211, Switzerland

    Robbie Loewith

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Contributions

D.B. and M.P. carried out most experiments, except lipidomics analyses (I.R., H.R.), and co-localization and membrane stretch experiments (M.P., N.C. and A.R.). R.L. and T.C.W. designed experiments, interpreted results and wrote the manuscript with contributions from all team members.

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Correspondence to Tobias C. Walther or Robbie Loewith.

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The authors declare no competing financial interests.

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Berchtold, D., Piccolis, M., Chiaruttini, N. et al. Plasma membrane stress induces relocalization of Slm proteins and activation of TORC2 to promote sphingolipid synthesis. Nat Cell Biol 14, 542–547 (2012). https://doi.org/10.1038/ncb2480

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