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 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] 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. 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. ^ 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. Bibcode:2021PNAS..11801410C. 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.

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