The mTOR pathway is the central regulator of cell size. 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 understood. Deregulation of the mTOR pathway occurs in polycystic kidney disease (PKD), where cilia (filiform sensory organelles) fail to sense urine flow because of inherited mutations in ciliary proteins. 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.
Bibliographical noteFunding Information:
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.