Primary cilia regulate mTORC1 activity and cell size through Lkb1

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

doi:10.1038/ncb2117

Cited by 339 publications

(313 citation statements)

References 45 publications

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“…Interestingly, previous reports have shown that myosin II motor inhibition with the Rho-kinase inhibitor Y27632 abolishes the flow-induced calcium response of murine epithelial kidney cells (46). Furthermore, there is evidence that the Lkb1 pathway in mammalian target-of-rapamycin signaling is locally activated at the cilia basal body through ciliary flow sensing, highlighting another possible physiological role for ciliary fluctuations (10).…”

Section: Discussionmentioning

confidence: 99%

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Intracellular and extracellular forces drive primary cilia movement

Battle

Ott

Burnette

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Primary cilia are ubiquitous, microtubule-based organelles that play diverse roles in sensory transduction in many eukaryotic cells. They interrogate the cellular environment through chemosensing, osmosensing, and mechanosensing using receptors and ion channels in the ciliary membrane. Little is known about the mechanical and structural properties of the cilium and how these properties contribute to ciliary perception. We probed the mechanical responses of primary cilia from kidney epithelial cells [Madin-Darby canine kidney-II (MDCK-II)], which sense fluid flow in renal ducts. We found that, on manipulation with an optical trap, cilia deflect by bending along their length and pivoting around an effective hinge located below the basal body. The calculated bending rigidity indicates weak microtubule doublet coupling. Primary cilia of MDCK cells lack interdoublet dynein motors. Nevertheless, we found that the organelles display active motility. 3D tracking showed correlated fluctuations of the cilium and basal body. These angular movements seemed random but were dependent on ATP and cytoplasmic myosin-II in the cell cortex. We conclude that force generation by the actin cytoskeleton surrounding the basal body results in active ciliary movement. We speculate that actin-driven ciliary movement might tune and calibrate ciliary sensory functions.

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Section: Discussionmentioning

confidence: 99%

“…1A). It has also been shown that ciliary mechanosensation regulates kidney epithelial cell size through the mammalian target-of-rapamycin pathway independent of Ca 2+ transients (10). How do the mechanical properties of the cilium facilitate these cellular responses?…”

mentioning

confidence: 99%

Intracellular and extracellular forces drive primary cilia movement

Battle

Ott

Burnette

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, the possibility exists that altered Mchr1 signaling in the absence of cilia in the Ift88 mutants, or due to its exclusion from the cilia in the Bbs mutants, could result in hyperphagia induced obesity. Cilia loss alters mTOR activity, which has a well-documented role in energy homeostasis (44)(45)(46); however, altered mTor has not been evaluated in the Bbs mutant mice. Further, treatment of cilia mutant mice with rapamycin can partially correct some mutant phenotypes (47).…”

Section: Discussionmentioning

confidence: 99%

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Berbari¹,

Pasek²,

Malarkey³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.

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“…Epithelial cells lining the cysts expressing mutated PC1 protein have increased levels of cell proliferation and abnormally activated mTOR signaling because of a disrupted interaction between PC1 and tuberin, a product of TSC2 gene, which controls mTOR activity. 91 Boehlke et al 92 showed that in kidney epithelial cells, the ciliary axoneme-dependent Lkb1/AMPactivated protein kinase (AMPK) pathway controls cell volume upstream of the inhibition of the mTOR pathway. In non-ciliated cystic renal epithelial cells, or cell lines with mutations in ciliogenesis-related proteins, this regulation of cell volume is Figure 3 Autophagy as a novel modulator of ciliogenesis.…”

Section: Autophagy and Ciliummentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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Primary cilia regulate mTORC1 activity and cell size through Lkb1

Cited by 339 publications

References 45 publications

Intracellular and extracellular forces drive primary cilia movement

Intracellular and extracellular forces drive primary cilia movement

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Autophagy and regulation of cilia function and assembly

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