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

Wang, Juan; Nikonorova, Inna A.; Silva, Malan; Walsh, Jonathon; Tilton, Peter; Gu, Amanda; Akella, Jyothi S.; Barr, Maureen M.

doi:10.1016/j.cub.2021.06.040

Cited by 46 publications

(55 citation statements)

References 60 publications

(48 reference statements)

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“…Based on in vivo fluorescent protein-tagging and imaging, none of the newly discovered cargoes co-localized to PKD-2 on ciliary EVs, indicating great complexity and heterogeneity of the EV mixture that co-purifies with PKD-2 EVs. Our results show that EVs shed by different neuronal types carry distinct EV cargo and corroborate our previous report that a single neuronal cilium may shed multiple cargoes [13].…”

Section: Discussionsupporting

confidence: 92%

Tracking extracellular vesicle (EV) cargo as a platform for studying EVomics, signaling, and targeting in vivo

Nikonorova

Wang

Cope

et al. 2021

Preprint

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Extracellular vesicle (EV)-based signaling is a challenge to study, due to EV small size, heterogeneity, and limited information on cargo content in vivo. We present Caenorhabditis elegans as a discovery platform that allows single EV tracking from source to target tissue in living animals. We enriched ciliary EVs using GFP-tagged PKD-2 cargo followed by mass spectrometry analysis to identify 2,888 cargo candidates. By integrating our dataset with single-cell transcriptomic data, we identified EV cargo produced by individual neurons and other cell and tissue types. A single cilium produces multiple EVs with distinct protein content. Ciliary EVs carry nucleic acid binding proteins. We observed transfer of EV cargo from the male reproductive tract to the hermaphrodite uterus during mating, a direct demonstration of animal-to-animal EV targeting.

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Section: Discussionsupporting

confidence: 92%

Tracking extracellular vesicle (EV) cargo as a platform for studying EVomics, signaling, and targeting in vivo

Nikonorova

Wang

Cope

et al. 2021

Preprint

Self Cite

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“…Several early arguments suggested that EVs produced by C. elegans males correspond to ectosomes shed from the cilia of the male neurons (Wang et al, 2014). Simultaneous to what we describe, new observations suggested that ciliary ectosomes may be shed from two sites of the cilia of CEM neurons (Wang et al, 2021). Our results confirm and extend these conclusions: many -potentially allhermaphrodite ciliated neurons can produce ciliary ectosomes from their cilia when ciliary membrane proteins are overexpressed.…”

Section: Discussionsupporting

confidence: 89%

Ectocytosis prevents accumulation of ciliary cargo in C. elegans sensory neurons

Razzauti

Laurent

2021

eLife

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Cilia are sensory organelles protruding from cell surfaces. Release of Extracellular Vesicles (EVs) from cilia was previously observed in mammals, Chlamydomonas, and in male C. elegans. Using the EV marker TSP-6 (an ortholog of mammalian CD9) and other ciliary receptors, we show that EVs are formed from ciliated sensory neurons in C. elegans hermaphrodites. Release of EVs is observed from two ciliary locations: the cilia tip and/or Periciliary Membrane Compartment (PCMC). Outward budding of EVs from the cilia tip leads to their release into the environment. EVs budding from the PCMC are concomitantly phagocytosed by the associated glial cells. To maintain cilia composition, a tight regulation of cargo import and removal is achieved by the action of Intra-Flagellar Transport (IFT). Unbalanced IFT due to cargo overexpression or mutations in the IFT machinery leads to local accumulation of ciliary proteins. Disposal of excess ciliary proteins via EVs reduces their local accumulation and exports them to the environment and/or to the glia associated to these ciliated neurons. We suggest that EV budding from cilia subcompartments acts as a safeguard mechanism to remove deleterious excess of ciliary material.

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“…Cilia-derived ectosomes contain biologically active molecules and have multiple functions in the regulation of ciliary signaling 19 , 21 , 23 , 24 , 43 , 44 . From the ciliary proteomics data, we noticed that the amount of ectosome-related proteins was disrupted in the cilia of mutant cells (e.g., FOX1, AGG3, FEA2, AGG4, FAP212, CYN20-1) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ciliary transition zone proteins coordinate ciliary protein composition and ectosome shedding

et al. 2022

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The transition zone (TZ) of the cilium/flagellum serves as a diffusion barrier that controls the entry/exit of ciliary proteins. Mutations of the TZ proteins disrupt barrier function and lead to multiple human diseases. However, the systematic regulation of ciliary composition and signaling-related processes by different TZ proteins is not completely understood. Here, we reveal that loss of TCTN1 in Chlamydomonas reinhardtii disrupts the assembly of wedge-shaped structures in the TZ. Proteomic analysis of cilia from WT and three TZ mutants, tctn1, cep290, and nphp4, shows a unique role of each TZ subunit in the regulation of ciliary composition, explaining the phenotypic diversity of different TZ mutants. Interestingly, we find that defects in the TZ impair the formation and biological activity of ciliary ectosomes. Collectively, our findings provide systematic insights into the regulation of ciliary composition by TZ proteins and reveal a link between the TZ and ciliary ectosomes.

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

Cited by 46 publications

References 60 publications

Tracking extracellular vesicle (EV) cargo as a platform for studying EVomics, signaling, and targeting in vivo

Tracking extracellular vesicle (EV) cargo as a platform for studying EVomics, signaling, and targeting in vivo

Ectocytosis prevents accumulation of ciliary cargo in C. elegans sensory neurons

Ciliary transition zone proteins coordinate ciliary protein composition and ectosome shedding

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