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Primary cilia regulate mTORC1 activity and cell size through Lkb1

Nature Cell Biology volume 12, pages 1115–1122 (2010)Cite this article

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Abstract

The mTOR pathway is the central regulator of cell size1. External signals from growth factors and nutrients converge on the mTORC1 multi-protein complex to modulate downstream targets, but how the different inputs are integrated and translated into specific cellular responses is incompletely understood2,3,4. Deregulation of the mTOR pathway occurs in polycystic kidney disease (PKD)5,6,7, where cilia (filiform sensory organelles) fail to sense urine flow because of inherited mutations in ciliary proteins8. We therefore investigated if cilia have a role in mTOR regulation. Here, we show that ablation of cilia in transgenic mice results in enlarged cells when compared with control animals. In vitro analysis demonstrated that bending of the cilia by flow is required for mTOR downregulation and cell-size control. Surprisingly, regulation of cell size by cilia is independent of flow-induced calcium transients, or Akt. However, the tumour-suppressor protein Lkb1 localises in the cilium, and flow results in increased AMPK phosphorylation at the basal body. Conversely, knockdown of Lkb1 prevents normal cell-size regulation under flow conditions. Our results demonstrate that the cilium regulates mTOR signalling and cell size, and identify the cilium-basal body compartment as a spatially restricted activation site for Lkb1 signalling.

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Figure 1: Cilia regulate cell size under flow conditions.
Figure 2: Cilia and flow modulate mTORC1 activity.
Figure 3: Flow-induced cell-size regulation is mTOR dependent and ablation of flow-induced calcium transients has no effect on cell size.
Figure 4: Lkb1 modulates flow-dependent mTOR and cell-size regulation and is localized in the basal body and the cilium.
Figure 5: Phosphorylated AMPK is localized at the basal body and increases under flow.

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Acknowledgements

This work was supported by grants DFG KFO 201 (to E.W.K.), WA597 and SFB 592 (to G.W.), SFB 592 Z2 and by the Excellence Initiative of the German Federal and State Governments (EXC 294 to R.N.), and NIH grants P30DK79328, R01DK67565 and T32DK07257 (to P.I.). We thank B. Yoder for anti-sera, R. Lamb, H. Clevers, Y. Mimori-Kiyosue, M. Sebbagh and A. Miyawaki for constructs, S. Arnold, M. Simons, D. Bennet and M. Bloech for critical appraisal of the manuscript and S. Lienkamp, F. Grahammer and members of the Walz lab for helpful discussions.

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  1. Christopher Boehlke and Fruzsina Kotsis: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Renal Unit, University Medical Center, Albert-Ludwig-University of Freiburg, Hugstetter Strasse 55, D-79106, Freiburg, Germany

    Christopher Boehlke, Fruzsina Kotsis, Simone Braeg, Henriette Voelker, Saskia Bredt, Theresa Beyer, Heike Janusch, Christoph Hamann, Markus Gödel, Klaus Müller, Martin Herbst, Miriam Hornung, Mara Doerken, Michael Köttgen, Gerd Walz & E. Wolfgang Kuehn

  2. Division of Nephrology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd, MC8856, Dallas, 75390-8856, TX, USA

    Vishal Patel & Peter Igarashi

  3. Life Imaging Center, Center for Biological Systems Analysis, Albert-Ludwig-University of Freiburg, Habsburgerstrasse 49, D-79104, Freiburg, Germany

    Roland Nitschke

  4. Center for Biological Signalling Studies (BIOSS), Albert-Ludwigs-University, D-79108, Freiburg, Germany

    Roland Nitschke

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Contributions

C.B., F.K., V.P., Si.B., H.V., Sa.B, T.B., H.J., C.H., K.M., Ma.H., Mi.H., M.D. and R.N. performed experiments. M.G. provided reagents. M.K., R.N., P.I., G.W. and E.W.K. conceived and planned the experiments and interpreted data. C.B., F.K. and E.W.K. wrote the manuscript.

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Correspondence to E. Wolfgang Kuehn.

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Boehlke, C., Kotsis, F., Patel, V. et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat Cell Biol 12, 1115–1122 (2010). https://doi.org/10.1038/ncb2117

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