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Establishing and regulating the composition of cilia for signal transduction


The primary cilium is a hair-like surface-exposed organelle of the eukaryotic cell that decodes a variety of signals — such as odorants, light and Hedgehog morphogens — by altering the local concentrations and activities of signalling proteins. Signalling within the cilium is conveyed through a diverse array of second messengers, including conventional signalling molecules (such as cAMP) and some unusual intermediates (such as sterols). Diffusion barriers at the ciliary base establish the unique composition of this signalling compartment, and cilia adapt their proteome to signalling demands through regulated protein trafficking. Much progress has been made on the molecular understanding of regulated ciliary trafficking, which encompasses not only exchanges between the cilium and the rest of the cell but also the shedding of signalling factors into extracellular vesicles.

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Fig. 1: Organization of primary cilia and photoreceptors.
Fig. 2: Transport processes that shape the ciliary environment.
Fig. 3: Models of transition zone crossing and of the intermediate compartment.
Fig. 4: Modalities and mechanisms of ciliary ectocytosis.


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The authors thank B. Snell, G. Witman, J. Reiter, M. Delling, D. Breslow, I. Ojeda Naharros and S. Shinde for comments on the manuscript and A. Nager for help with drafting the manuscript. They apologize to their colleagues whose publications they could not cite owing to length restrictions. Research in the Nachury laboratory is supported by NIGMS grant GM089933, a Stein Innovation Award from Research to Prevent Blindness and, in part, by NEI core grant EY002162 and by an RPB Unrestricted Grant. Research in the Mick laboratory is supported by the Deutsche Forschungsgemeinschaft (DFG) SFB894/TPA-22.

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Nature Reviews Molecular Cell Biology thanks L. B. Pedersen and other anonymous reviewer(s) for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

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Correspondence to Maxence V. Nachury.

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G protein-coupled receptors

(GPCRs). Membrane proteins with seven transmembrane domains that sense various external signals (such as drugs and odorants) and relay them into the cell through heterotrimeric G proteins.


Refers to an effect related to the loss of appetite (anorexia), thus resulting in lower food consumption and weight loss.


Sensory neurons that detect light using rhodopsin localized inside a specialized cilium.


A photosensory G protein-coupled receptor (GPCR) that transduces light using a tightly bound molecule of retinal.

Bardet–Biedl syndrome

(BBS). A ciliopathy (with mutations in 21 different genes identified to date) characterized by retinal degeneration, obesity, kidney abnormalities and polydactyly.


Hallmark lipids that mark the cytoplasmic leaflets of cellular membranes.

Basal body

A specialized mother centriole that is a template for the ciliary axoneme.


The microtubule core of cilia composed of nine microtubule doublets.

Transition fibres

Identical to the distal appendages of mother centrioles in unciliated cells, transition fibres physically connect the basal body to the membrane in ciliated cells.


Y-shaped electron-dense structures that connect the ciliary axoneme (bottom of the Y) to the membrane (top of the Y) at the transition zone.

Tight junctions

The junctions between adjacent epithelial cells that seal the epithelium and function as a barrier for lipid and integral membrane protein diffusion between the apical and basolateral membranes of cells.

Heterotrimeric G protein α subunit

The GTPase subunit of heterotrimeric G proteins. It becomes loaded with GTP after encountering an active G protein-coupled receptor (GPCR) and modulates downstream activities, such as adenylyl cyclases. Gαs–GTP stimulates adenylyl cyclases, while Gαi–GTP inhibits them.

GLI transcription factors

The GLI1 transcription activator was first identified in glioblastoma (a Hedgehog-driven tumour). The paralogues GLI2 and GLI3 are processed into transcription activators or repressors depending upon regulatory inputs from the Hedgehog pathway.


Lipids formed by a backbone that consists of a sphingosine N-acylated by a fatty acid. Named after the Sphinx because of their once-enigmatic functions.


Products of cholesterol oxidation with hydroxyl, carbonyl or epoxide groups. Their best-established roles are in regulation of cholesterol metabolism.

Condensed membrane microdomains

Tightly packed and viscous regions of the membrane that can form through clustering of lipid rafts.

Liquid-ordered lipid phase

Biological membranes are two-dimensional liquids that can phase separate into liquid-ordered (for example, rafts) and liquid-disordered (for example, fluid mosaic) phases.


A relatively ordered membrane domain formed by interactions between proteins and lipids. Rafts typically present as cholesterol and sphingolipidenriched membrane nanodomains <200 nm in size that are thought to facilitate interactions between signalling molecules.


A complex of eight Bardet–Biedl syndrome proteins that removes proteins from cilia.

IFT trains

High-order oligomers of intraflagellar transport (IFT) complexes that transport cargo along the axoneme.

Polycystic kidney and hepatic disease 1

(PKHD1). A large single-pass membrane protein of unknown function mutated in autosomal recessive polycystic kidney disease.

Ciliary targeting signal

(CTS). In the strictest sense, a short stretch of amino acids that is necessary and sufficient for targeting a protein to cilia. Some CTSs (for example, in somatostatin receptor 3) are sufficient but not necessary for ciliary targeting.

Somatostatin receptor 3

(SSTR3). A ciliary G protein-coupled receptor (GPCR) expressed in hippocampal neurons and required for novelty recognition. It couples to Gαi.

Melanocortin concentrating hormone receptor 1

(MCHR1). A ciliary G protein-coupled receptor (GPCR) that has a modest role in body weight homeostasis.


A small GTPase of the ARF-like family, most members of which regulate vesicular trafficking.

β-Arrestin 2

Recognizes activated G protein-coupled receptors (GPCRs), blocks GPCR-to-Gα communication and promotes GPCR endocytosis, thereby typically driving termination of GPCR signalling.

Axon initial segment

In neurons, the first few micrometres of the axon. It is an area rich in actin that functionally separates the axonal plasma membrane from the soma plasma membrane.


Nuclear transport receptors that ferry proteins across the nuclear pore complex.


Extracellular vesicles that directly bud from the limiting membrane of the cell. Also termed microvesicles.

Neuropeptide Y receptor type 2

(NPY2R). A Gαs-coupled G protein-coupled receptor (GPCR) that regulates appetite under stress conditions.


Extracellular vesicles that originate as vesicles inside the lumen of the multivesicular body and become extracellular upon fusion of the multivesicular body with the plasma membrane.

Endosomal sorting complex required for transport

(ESCRT). A cascade of protein complexes (0, I, II and III in order of action) discovered initially in yeast as factors involved in budding transmembrane proteins from the endosomal membrane into intraluminal vesicles. ESCRTs have since been demonstrated to be necessary for many cellular processes involving a bud-like topology.

Line tension

The 2D version of surface tension, which reflects the energy minimization of a system in which an energetically costly discontinuity exists between two neighbouring phases.

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Nachury, M.V., Mick, D.U. Establishing and regulating the composition of cilia for signal transduction. Nat Rev Mol Cell Biol 20, 389–405 (2019).

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