Exopher

Multiple exophers produced by a mechanosensory neuron in C. elegans

Exophers are a type of membrane-bound extracellular vesicle (EV) that are released by budding out of cells into the extracellular space. Exophers can be released by neurons[1] and muscle[2] in the nematode Caenorhabditis elegans and also from murine cardiomyocytes.[3] Exophers were first discovered in 2017 by an undergraduate student in the lab of Monica Driscoll at Rutgers University.[4]

Exophers are notable for their large size, averaging approximately four microns in diameter, and they are able to expel whole organelles, such as mitochondria and lysosomes as cargo.[1] An exopher can initially remain attached to the cell that produced it by a membranous filament that resembles a tunneling nanotube. Exophers share similarities with large oncosomes, but they differ in that they are produced by physiologically normal cells instead of aberrant cells associated with tumors.[5]

Exopher production is thought to be a mechanism cells use to preserve homeostasis. Exophers are produced in response to numerous stressors including intracellular protein aggregation, reactive oxygen species (ROS),[1] heat, osmotic hyertonicity, starvation,[6] and even space flight.[7] Mechanistically, exopher production has been found to depend on extracellular receptor signaling. Two MAPK pathways, epidermal growth factor (EGF) and fibroblast growth factor (FGF) signaling have been implicated in exopher production in nematodes.[6] Extracellular signaling receptor MERTK, expressed by cardiac-resident macrophages, is necessary for exopher clearance by phagocytosis in mouse-derived cardiac tissue.[3]

Exophers may be relevant to disease. In mouse heart, eliminating macrophages or blocking their ability to engulf exophers lead to inflammation and ventricular dysregulation.[3] Exophers may also promote pathological protein spreading in neurodegenerative diseases due to their ability to carry aggregated proteins outside of neurons, including human huntingtin protein.[1]

References

  1. ^ a b c d Melentijevic, I; Toth, ML; Arnold, ML; Guasp, RJ; Harinath, G; Nguyen, KC; Taub, D; Parker, JA; Neri, C; Gabel, CV; Hall, DH; Driscoll, M (2017). "C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress". Nature. 542(7641) (7641): 367–371. Bibcode:2017Natur.542..367M. doi:10.1038/nature21362. PMC 5336134. PMID 28178240.
  2. ^ Turek, M; Banasiak, K; Piechota, M; Shanmugam, N; Macias, M; Śliwińska, MA; Niklewicz, M; Kowalski, K; Nowak, N; Chacinska, A; Pokrzywa, P (2021). "Muscle-derived exophers promote reproductive fitness". EMBO Rep. 22 (8): e52071. doi:10.15252/embr.202052071. PMC 8339713. PMID 34288362.
  3. ^ a b c Nicolás-Ávila JA, Lechuga-Vieco AV, Esteban-Martínez L, Sánchez-Díaz M, Díaz-García E, Santiago DJ, et al. (2020). "A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart". Cell. 183 (1): 94–109. doi:10.1016/j.cell.2020.08.031. hdl:10261/226682. PMID 32937105. S2CID 221716195.
  4. ^ Neff, Ellen P. (2017-04-19). "C. elegans takes out the trash". Lab Animal. 46 (5): 189–189. doi:10.1038/laban.1264. ISSN 1548-4475.
  5. ^ Meehan B, Rak J, Di Vizio D (2016). "Oncosomes - large and small: what are they, where they came from?". Journal of Extracellular Vesicles. 5: 33109. doi:10.3402/jev.v5.33109. PMC 5040817. PMID 27680302.
  6. ^ a b Cooper, JF; Guasp, RJ; Arnold, ML; Grant, BD; Driscoll, M (2021). "Stress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling". Proc Natl Acad Sci USA. 118 (36): e2101410118. doi:10.1073/pnas.2101410118. PMC 8433523. PMID 34475208.
  7. ^ Laranjeiro R, Harinath G, Pollard AK, Gaffney CJ, Deane CS, Vanapalli SA, Etheridge T, Szewczyk NJ, Driscoll M (2021). "Spaceflight affects neuronal morphology and alters transcellular degradation of neuronal debris in adult Caenorhabditis elegans". iScience. 24 (2): 102105. Bibcode:2021iSci...24j2105L. doi:10.1016/j.isci.2021.102105. hdl:10871/126285. PMC 7890410. PMID 33659873.