Ciliary intrinsic mechanisms regulate dynamic ciliary extracellular vesicle release from sensory neurons

Abstract

SummaryCilia-derived extracellular vesicles (EVs) contain signaling proteins and act in intercellular communication. Polycystin-2 (PKD-2), a transient receptor potential channel, is a conserved ciliary EVs cargo.Caenorhabditis elegansserves as a model for studying ciliary EV biogenesis and function.C. elegansmales release EVs in a mechanically-induced manner and deposit PKD-2-labeled EVs onto the hermaphrodite vulva during mating, suggesting an active release process. Here, we study the dynamics of ciliary EV release using time-lapse imaging and find that cilia can sustain the release of PKD-2-labeled EVs for a two-hour duration. Intriguingly, this extended release doesn’t require neuronal synaptic transmission. Instead, ciliary intrinsic mechanisms regulate PKD-2 ciliary membrane replenishment and dynamic EV release. The ciliary kinesin-3 motor KLP-6 is necessary for both initial and extended ciliary EV release, while the transition zone protein NPHP-4 is required only for sustained EV release. The dihydroceramide desaturase DEGS1/2 ortholog TTM-5 is highly expressed in the EV-releasing sensory neurons, localizes to cilia, and is required for sustained but not initial ciliary EV release, implicating ceramide in ciliary ectocytosis. The study offers a comprehensive portrait of real-time ciliary EV release, and mechanisms supporting cilia as proficient EV release platforms.

Loss of KIF13B causes time-dependent changes in ciliary polycystin-2 levels and extracellular vesicle release

“…Furthermore, since KIF13B was shown to regulate ciliary localization of CAV1 and interacted with NPHP4 at the ciliary transition zone (Schou et al, 2017), a more direct role for KIF13B-CAV1-NPHP4 interactions in promoting ciliary membrane homeostasis and EV release can be envisioned. In this context we note that mutations in NPHP4 were shown to affect ciliary EV release in C. reinhardtii (Wang et al, 2022) and C. elegans (Wang et al, 2023a), and CAV1 was implicated in ciliary PC2 homeostasis in C. elegans (Scheidel et al, 2018) and in EV biogenesis in other contexts (Ariotti et al, 2021).…”

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

“…The mechanism by which the primary cilium, located at the nociceptor cell soma, contributes to the transduction of mechanical stimuli and nociceptor sensitization, in the setting of inflammatory and neuropathic pain at the peripheral terminal of the nociceptor, a long distance from the cell body, and whether the nociceptor primary cilium contributes to the detection of other noxious stimuli (e.g., noxious heat and cold, and pain-produced by noxious chemicals such as capsaicin) remains to be established. As the central terminal of the nociceptor, located in the dorsal horn of the spinal cord, is involved in neurotransmission, to second order neurons in pain circuitry, a possible role of primary cilia in pain neurotransmission, established in the central nervous system [64][65][66] , should also be considered in nociceptors.…”