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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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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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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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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DOI: https://doi.org/10.1038/ncb2480