The molecular structure of mammalian primary cilia revealed by cryo-electron tomography

Kiesel, Petra; Viar, Gonzalo Alvarez; Tsoy, Nikolai; Maraspini, Riccardo; Gorilák, Peter; Varga, Vladimír; Honigmann, Alf; Pigino, Gaia

doi:10.1038/s41594-020-0507-4

Cited by 144 publications

(157 citation statements)

References 73 publications

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“…This study identified bundles of actin close to the ciliary membrane and a structure resembling F-actin that intertwined with microtubules within the ciliary axoneme ( Kiesel et al, 2020 ). These localizations were supported by immunofluorescence microscopy imaging with phalloidin and are consistent with a functional role of F-actin in maintaining the organization of the ciliary axoneme ( Kiesel et al, 2020 ). Cryo-ET studies of the organization and molecular architecture of the primary cilium remain in their infancy, and there will undoubtedly be many further insights and surprises as cryo-ET workflows become integrated with correlated light microscopy studies of individual ciliary proteins.…”

Section: Cilia and The Actin Cytoskeletonmentioning

confidence: 94%

“…Other reports have also highlighted the involvement of F-actin in both ciliary decapping ( Phua et al, 2017 ) and ectosome excision ( Nager et al, 2017 ) suggesting that actin might play a functional role within cilia, although it is notable that these studies did not identify possible actin-severing molecules that could reduce the length of actin filaments and mediate excision events. Direct detection of actin in cilia, at molecular resolution, has only recently been possible by using cryo-electron tomography (cryo-ET) preparations of primary cilia ( Kiesel et al, 2020 ). This study identified bundles of actin close to the ciliary membrane and a structure resembling F-actin that intertwined with microtubules within the ciliary axoneme ( Kiesel et al, 2020 ).…”

Section: Cilia and The Actin Cytoskeletonmentioning

confidence: 99%

“…Direct detection of actin in cilia, at molecular resolution, has only recently been possible by using cryo-electron tomography (cryo-ET) preparations of primary cilia ( Kiesel et al, 2020 ). This study identified bundles of actin close to the ciliary membrane and a structure resembling F-actin that intertwined with microtubules within the ciliary axoneme ( Kiesel et al, 2020 ). These localizations were supported by immunofluorescence microscopy imaging with phalloidin and are consistent with a functional role of F-actin in maintaining the organization of the ciliary axoneme ( Kiesel et al, 2020 ).…”

Section: Cilia and The Actin Cytoskeletonmentioning

confidence: 99%

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Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

Smith

Lake

Johnson

2020

Front. Cell Dev. Biol.

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Primary cilia are microtubule-based organelles that extend from the apical surface of most mammalian cells, forming when the basal body (derived from the mother centriole) docks at the apical cell membrane. They act as universal cellular “antennae” in vertebrates that receive and integrate mechanical and chemical signals from the extracellular environment, serving diverse roles in chemo-, mechano- and photo-sensation that control developmental signaling, cell polarity and cell proliferation. Mutations in ciliary genes cause a major group of inherited developmental disorders called ciliopathies. There are very few preventative treatments or new therapeutic interventions that modify disease progression or the long-term outlook of patients with these conditions. Recent work has identified at least four distinct but interrelated cellular processes that regulate cilia formation and maintenance, comprising the cell cycle, cellular proteostasis, signaling pathways and structural influences of the actin cytoskeleton. The actin cytoskeleton is composed of microfilaments that are formed from filamentous (F) polymers of globular G-actin subunits. Actin filaments are organized into bundles and networks, and are attached to the cell membrane, by diverse cross-linking proteins. During cell migration, actin filament bundles form either radially at the leading edge or as axial stress fibers. Early studies demonstrated that loss-of-function mutations in ciliopathy genes increased stress fiber formation and impaired ciliogenesis whereas pharmacological inhibition of actin polymerization promoted ciliogenesis. These studies suggest that polymerization of the actin cytoskeleton, F-actin branching and the formation of stress fibers all inhibit primary cilium formation, whereas depolymerization or depletion of actin enhance ciliogenesis. Here, we review the mechanistic basis for these effects on ciliogenesis, which comprise several cellular processes acting in concert at different timescales. Actin polymerization is both a physical barrier to both cilia-targeted vesicle transport and to the membrane remodeling required for ciliogenesis. In contrast, actin may cause cilia loss by localizing disassembly factors at the ciliary base, and F-actin branching may itself activate the YAP/TAZ pathway to promote cilia disassembly. The fundamental role of actin polymerization in the control of ciliogenesis may present potential new targets for disease-modifying therapeutic approaches in treating ciliopathies.

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Section: Cilia and The Actin Cytoskeletonmentioning

confidence: 94%

Section: Cilia and The Actin Cytoskeletonmentioning

confidence: 99%

Section: Cilia and The Actin Cytoskeletonmentioning

confidence: 99%

See 1 more Smart Citation

Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

Smith

Lake

Johnson

2020

Front. Cell Dev. Biol.

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“…Interestingly, evidence from cryo-electron tomography and subtomogram averaging reveals the appearance of the anterograde IFT trains along the A-tubule singlets in primary cilia of Madin-Darby Canine Kidney (MDCK) epithelial cells. This suggests different mechanisms of transport between the motile cilia and the primary cilia (Kiesel et al, 2020). Glutamylation statuses and the consequent effects on the A-tubule singlets in primary cilia still remain to be clarified.…”

Section: The Roles Of Glutamylation In Ift Dynamicsmentioning

confidence: 99%

The Emerging Roles of Axonemal Glutamylation in Regulation of Cilia Architecture and Functions

Yang

Hong

et al. 2021

Front. Cell Dev. Biol.

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Cilia, which either generate coordinated motion or sense environmental cues and transmit corresponding signals to the cell body, are highly conserved hair-like structures that protrude from the cell surface among diverse species. Disruption of ciliary functions leads to numerous human disorders, collectively referred to as ciliopathies. Cilia are mechanically supported by axonemes, which are composed of microtubule doublets. It has been recognized for several decades that tubulins in axonemes undergo glutamylation, a post-translational polymodification, that conjugates glutamic acid chains onto the C-terminal tail of tubulins. However, the physiological roles of axonemal glutamylation were not uncovered until recently. This review will focus on how cells modulate glutamylation on ciliary axonemes and how axonemal glutamylation regulates cilia architecture and functions, as well as its physiological importance in human health. We will also discuss the conventional and emerging new strategies used to manipulate glutamylation in cilia.

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“…In cultured mammalian cells, ciliary EVs regulate ciliary disposal but also receptor abundance and signaling, ciliary length, and ciliary membrane dynamics 9–11,15 . Mammalian cilia appear to produce EVs from the tip and along the ciliary membrane 16,17 . However, the functional significance of shedding at the distinct locations, as well as molecular mechanisms that regulate ciliary EV biogenesis remain elusive.…”

Section: Mainmentioning

confidence: 99%

Sensory cilia act as a specialized venue for regulated EV biogenesis and signaling

Wang

Silva

et al. 2021

Preprint

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Extracellular vesicles play major roles in intercellular signaling, yet fundamental aspects of their biology remain poorly understood. Ciliary EV shedding is evolutionary conserved. Here we use super resolution,real time imaging of fluorescent-protein tagged EV cargo combined with in vivo bioassays to study signaling EVs in C. elegans. We find that neuronal sensory cilia shed the TRP polycystin-2 channel PKD-2::GFP-carrying EVs from two distinct sites - the ciliary tip and the ciliary base. Ciliary tip shedding requires distal ciliary enrichment of PKD-2 by the myristoylated coiled-coil protein CIL-7. Kinesin-3 KLP-6 and intraflagellar transport (IFT) kinesin-2 motors are also required for ciliary tip EV shedding. Blocking ciliary tip shedding results in excessive EV shedding from the base. Finally, we demonstrate that C. elegans male ciliated neurons modulate EV cargo composition in response to sensory stimulation by hermaphrodite mating partners. Overall, our study indicates that the cilium and its trafficking machinery act as a specialized venue for regulated EV biogenesis and signaling.

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The molecular structure of mammalian primary cilia revealed by cryo-electron tomography

Cited by 144 publications

References 73 publications

Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

The Emerging Roles of Axonemal Glutamylation in Regulation of Cilia Architecture and Functions

Sensory cilia act as a specialized venue for regulated EV biogenesis and signaling

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