Large vesicle extrusions from C. elegans neurons are consumed and stimulated by glial-like phagocytosis activity of the neighboring cell
C. elegans neurons under stress can produce giant vesicles, several microns in diameter, called exophers. Current models suggest that exophers are neuroprotective, providing a mechanism for stressed neurons to eject toxic protein aggregates and organelles. However, little is known of the fate of the exopher once it leaves the neuron. We found that exophers produced by mechanosensory neurons in C. elegans are engulfed by surrounding hypodermal skin cells and are then broken up into numerous smaller vesicles that acquire hypodermal phagosome maturation markers, with vesicular contents gradually degraded by hypodermal lysosomes. Consistent with the hypodermis acting as an exopher phagocyte, we found that exopher removal requires hypodermal actin and Arp2/3, and the hypodermal plasma membrane adjacent to newly formed exophers accumulates dynamic F-actin during budding. Efficient fission of engulfed exopher-phagosomes to produce smaller vesicles and degrade their contents requires phagosome maturation factors SAND-1/Mon1, GTPase RAB-35, the CNT-1 ARF-GAP, and microtubule motor associated GTPase ARL-8, suggesting a close coupling of phagosome fission and phagosome maturation. Lysosome activity was required to degrade exopher contents in the hypodermis but not for exopher-phagosome resolution into smaller vesicles. Importantly, we found that GTPase ARF-6 and effector SEC-10/Exocyst activity in the hypodermis, along with the CED-1 phagocytic receptor, is required for efficient production of exophers by the neuron. Our results indicate that the neuron requires specific interaction with the phagocyte for an efficient exopher response, a mechanistic feature potentially conserved with mammalian exophergenesis, and similar to neuronal pruning by phagocytic glia that influences neurodegenerative disease.
All data generated or analysed during this study are included in the manuscript and supporting files; Source Data files have been provided for Figures 1-8 and S2-S6.
Article and author information
National Institutes of Health (R01AG047101)
- David H Hall
- Monica Driscoll
- Barth D Grant
National Institutes of Health (R24OD090143)
- David H Hall
National Institutes of Health (F31AG066405)
- Meghan Lee Arnold
National Institutes of Health (F31NS101969)
- Anna Joelle Smart
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Paschalis Kratsios, University of Chicago, United States
- Received: July 27, 2022
- Preprint posted: August 1, 2022 (view preprint)
- Accepted: February 28, 2023
- Accepted Manuscript published: March 2, 2023 (version 1)
- Version of Record published: March 17, 2023 (version 2)
© 2023, Wang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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