Primary cilia regulate mTORC1 activity and cell size through Lkb1.
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.
Renal Unit, Department of Medicine, University Medical Center, Albert-Ludwig-University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
Christopher
C
Boehlke
Fruzsina
F
Kotsis
Vishal
V
Patel
Simone
S
Braeg
Henriette
H
Voelker
Saskia
S
Bredt
Theresa
T
Beyer
Heike
H
Janusch
Christoph
C
Hamann
Markus
M
Gödel
Klaus
K
Müller
Martin
M
Herbst
Miriam
M
Hornung
Mara
M
Doerken
Michael
M
Köttgen
Roland
R
Nitschke
Peter
P
Igarashi
Gerd
G
Walz
E Wolfgang
EW
Kuehn
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D048429:Cell Size; D002923:Cilia / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D016547:Kinesins / Q000172:deficiency / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
C490202:Kif3a protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D016547:Kinesins; D002118:Calcium