Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

An emergency response team for membrane repair

Nature Reviews Molecular Cell Biology volume 6, pages 499–505 (2005)Cite this article

Abstract

On demand, rapid Ca2+-triggered homotypic and exocytic membrane-fusion events are required to repair a torn plasma membrane, and we propose that this emergency-based fusion differs fundamentally from other rapid, triggered fusion reactions. Emergency fusion might use a specialized protein and organelle emergency response team that can simultaneously promote impromptu homotypic fusion events between organelles and exocytic fusion events along the vertices between these fusion products and the plasma membrane.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Ca2+ dependence and dynamics of barrier formation at sites of membrane disruption in the sea-urchin egg.
Figure 2: Two possible resealing mechanisms.
Figure 3: 'Vertex fusion' and plasma-membrane restoration.

Similar content being viewed by others

References

  1. McNeil, P. L. & Khakee, R. Disruptions of muscle fiber plasma membranes. Role in exercise-induced damage. Am. J. Pathol. 140, 1097–1109 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Clarke, M. S., Caldwell, R. W., Chiao, H., Miyake, K. & McNeil, P. L. Contraction-induced cell wounding and release of fibroblast growth factor in heart. Circ. Res. 76, 927–934 (1995).

    Article  CAS  Google Scholar 

  3. Aumuller, G., Wilhelm, B. & Seitz, J. Apocrine secretion — fact or artifact? Anat. Anz. 181, 437–446 (1999).

    Article  CAS  Google Scholar 

  4. Geeraerts, M. D., Ronveaux-Dupal, M. F., Lemasters, J. J. & Herman, B. Cytosolic free Ca2+ and proteolysis in lethal oxidative injury in endothelial cells. Am. J. Physiol. 261, C889–C896 (1991).

    Article  CAS  Google Scholar 

  5. Steinhardt, R. A., Bi, G. & Alderton, J. M. Cell membrane resealing by a vesicular mechanism similar to neurotransmitter release. Science 263, 390–393 (1994).

    Article  CAS  Google Scholar 

  6. Hoffman, J. F. On red blood cells, hemolysis and resealed ghosts. Adv. Exp. Med. Biol. 326, 1–15 (1992).

    CAS  PubMed  Google Scholar 

  7. McNeil, P. L., Miyake, K. & Vogel, S. S. The endomembrane requirement for cell surface repair. Proc. Natl Acad. Sci. USA 100, 4592–4597 (2003).

    Article  CAS  Google Scholar 

  8. Freedman, J. C. et al. Membrane potential and the cytotoxic Ca cascade of human red blood cells. Soc. Gen. Physiol. Ser. 43, 217–231 (1988).

    CAS  PubMed  Google Scholar 

  9. Togo, T., Krasieva, T. B. & Steinhardt, R. A. A decrease in membrane tension precedes successful cell-membrane repair. Mol. Biol. Cell 11, 4339–4346 (2000).

    Article  CAS  Google Scholar 

  10. Sheetz, M. P. Cell control by membrane–cytoskeleton adhesion. Nature Rev. Mol. Cell Biol. 2, 392–396 (2001).

    Article  CAS  Google Scholar 

  11. Zhelev, D. V. & Needham, D. Tension-stabilized pores in giant vesicles: determination of pore size and pore line tension. Biochim. Biophys. Acta 1147, 89–104 (1993).

    Article  CAS  Google Scholar 

  12. Clarke, M. S. & McNeil, P. L. Syringe loading introduces macromolecules into living mammalian cell cytosol. J. Cell Sci. 102, 535–541 (1992).

    Google Scholar 

  13. Terasaki, M., Miyake, K. & McNeil, P. L. Large plasma membrane disruptions are rapidly resealed by Ca2+-dependent vesicle–vesicle fusion events. J. Cell Biol. 139, 63–74 (1997).

    Article  CAS  Google Scholar 

  14. McNeil, P. L. & Baker, M. M. Cell surface events during resealing visualized by scanning-electron microscopy. Cell Tissue Res. 304, 141–146 (2001).

    Article  CAS  Google Scholar 

  15. McNeil, P. L., Vogel, S. S., Miyake, K. & Terasaki, M. Patching plasma membrane disruptions with cytoplasmic membrane. J. Cell Sci. 113, 1891–1902 (2000).

    CAS  PubMed  Google Scholar 

  16. Miyake, K. & McNeil, P. L. Vesicle accumulation and exocytosis at sites of plasma membrane disruption. J. Cell Biol. 131, 1737–1745 (1995).

    Article  CAS  Google Scholar 

  17. Wang, L., Seeley, E. S., Wickner, W. & Merz, A. J. Vacuole fusion at a ring of vertex docking sites leaves membrane fragments within the organelle. Cell 108, 357–369 (2002).

    Article  CAS  Google Scholar 

  18. Wang, L., Merz, A. J., Collins, K. M. & Wickner, W. Hierarchy of protein assembly at the vertex ring domain for yeast vacuole docking and fusion. J. Cell Biol. 160, 365–374 (2003).

    Article  CAS  Google Scholar 

  19. Andrews, N. W. Lysosome recruitment during host cell invasion by Trypanosoma cruzi. Trends Cell Biol. 5, 133–137 (1995).

    Article  CAS  Google Scholar 

  20. Caler, E. V., Chakrabarti, S., Fowler, K. T., Rao, S. & Andrews, N. W. The exocytosis-regulatory protein synaptotagmin VII mediates cell invasion by Trypanosoma cruzi. J. Exp. Med. 193, 1097–1104 (2001).

    Article  CAS  Google Scholar 

  21. Reddy, A., Caler, E. V. & Andrews, N. W. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell 106, 157–169 (2001).

    Article  CAS  Google Scholar 

  22. Chakrabarti, S. et al. Impaired membrane resealing and autoimmune myositis in synaptotagmin VII-deficient mice. J. Cell Biol. 162, 543–549 (2003).

    Article  CAS  Google Scholar 

  23. Jaiswal, J. K., Chakrabarti, S., Andrews, N. W. & Simon, S. M. Synaptotagmin VII restricts fusion pore expansion during lysosomal exocytosis. PLoS Biol. 2, E233 (2004).

    Article  Google Scholar 

  24. Cerny, J. et al. The small chemical vacuolin-1 inhibits Ca2+-dependent lysosomal exocytosis but not cell resealing. EMBO Rep. 5, 883–888 (2004).

    Article  CAS  Google Scholar 

  25. Borgonovo, B. et al. Regulated exocytosis: a novel, widely expressed system. Nature Cell Biol. 4, 955–962 (2002).

    Article  CAS  Google Scholar 

  26. Cocucci, E., Racchetti, G., Podini, P., Rupnik, M. & Meldolesi, J. Enlargeosome, an exocytic vesicle resistant to nonionic detergents, undergoes endocytosis via a nonacidic route. Mol. Biol. Cell 15, 5356–5368 (2004).

    Article  CAS  Google Scholar 

  27. Rothman, J. E. Lasker basic medical research award. The machinery and principles of vesicle transport in the cell. Nature Med. 8, 1059–1062 (2002).

    Article  CAS  Google Scholar 

  28. Bi, G. Q., Alderton, J. M. & Steinhardt, R. A. Calcium-regulated exocytosis is required for cell membrane resealing. J. Cell Biol. 131, 1747–1758 (1995).

    Article  CAS  Google Scholar 

  29. Yoshihara, M., Adolfsen, B. & Littleton, J. T. Is synaptotagmin the calcium sensor? Curr. Opin. Neurobiol. 13, 315–323 (2003).

    Article  CAS  Google Scholar 

  30. Detrait, E. et al. Axolemmal repair requires proteins that mediate synaptic vesicle fusion. J. Neurobiol. 44, 382–391 (2000).

    Article  CAS  Google Scholar 

  31. Shen, S. S., Tucker, W. C., Chapman, E. R. & Steinhardt, R. A. Molecular regulation of membrane resealing in 3T3 fibroblasts. J. Biol. Chem. 280, 1652–1660 (2004).

    Article  Google Scholar 

  32. Merz, A. J. & Wickner, W. T. Resolution of organelle docking and fusion kinetics in a cell-free assay. Proc. Natl Acad. Sci. USA 101, 11548–11553 (2004).

    Article  CAS  Google Scholar 

  33. Chestkov, V. V., Radko, S. P., Cho, M. S., Chrambach, A. & Vogel, S. S. Reconstitution of calcium-triggered membrane fusion using 'reserve' granules. J. Biol. Chem. 273, 2445–2451 (1998).

    Article  CAS  Google Scholar 

  34. Sudhof, T. C. The synaptic vesicle cycle: a cascade of protein–protein interactions. Nature 22, 645–653 (1995).

    Article  Google Scholar 

  35. Murthy, V. N. & De Camilli, P. Cell biology of the presynaptic terminal. Annu. Rev. Neurosci. 26, 701–728 (2003).

    Article  CAS  Google Scholar 

  36. Bashir, R. et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nature Genet. 20, 37–42 (1998).

    Article  CAS  Google Scholar 

  37. Liu, J. et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nature Genet. 20, 31–36 (1998).

    Article  CAS  Google Scholar 

  38. Achanzar, W. E. & Ward, S. A nematode gene required for sperm vesicle fusion. J. Cell Sci. 110, 1073–1081 (1997).

    CAS  PubMed  Google Scholar 

  39. Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003).

    Article  CAS  Google Scholar 

  40. Papahadjopoulos, D., Nir, S. & Duzgunes, N. Molecular mechanisms of calcium-induced membrane fusion. J. Bioenerg. Biomembr. 22, 157–179 (1990).

    Article  CAS  Google Scholar 

  41. Lennon, N. J. et al. Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J. Biol. Chem. 278, 50466–50473 (2003).

    Article  CAS  Google Scholar 

  42. Davis, D. B., Delmonte, A. J., Ly, C. T. & McNally, E. M. Myoferlin, a candidate gene and potential modifier of muscular dystrophy. Hum. Mol. Genet. 9, 217–226 (2000).

    Article  CAS  Google Scholar 

  43. Chapman, E. R. Synaptotagmin: a Ca2+ sensor that triggers exocytosis? Nature Rev. Mol. Cell Biol. 3, 498–508 (2002).

    Article  CAS  Google Scholar 

  44. Bansal, D. & Campbell, K. P. Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol. 14, 206–213 (2004).

    Article  CAS  Google Scholar 

  45. Bai, J., Wang, C. T., Richards, D. A., Jackson, M. B. & Chapman, E. R. Fusion pore dynamics are regulated by synaptotagmin·t-SNARE interactions. Neuron 41, 929–942 (2004).

    Article  CAS  Google Scholar 

  46. Yasunaga, S. et al. A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nature Genet. 21, 363–369 (1999).

    Article  CAS  Google Scholar 

  47. McNeil, P. L. & Steinhardt, R. Plasma membrane disruption: repair, prevention, adaptation. Annu. Rev. Cell Dev. Biol. 3, 697–731 (2003).

    Article  Google Scholar 

  48. Bement, W. M., Mandato, C. A. & Kirsch, M. N. Wound-induced assembly and closure of an actomyosin purse string in Xenopus oocytes. Curr. Biol. 9, 579–587 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Merz for suggesting how vertex fusion might explain the patch exocytosis, and K. Miyake for the images used in Figure 1. P.L.M. is funded by National Aeronautics and Space Administration, and T.K. is funded by the National Institutes of Health. Due to space limitations, reviews have been cited in the place of original publications on several occasions.

Author information

Authors and Affiliations

  1. the Department of Anatomy and Cellular Biology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, 30921, Georgia, USA

    Paul L. McNeil

  2. the Department of Cell Biology, Harvard Medical School and the CBR Institute of Biomedical Research, Boston, 02135, Massachusetts, USA

    Tom Kirchhausen

Authors
  1. Paul L. McNeil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tom Kirchhausen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul L. McNeil.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

41580_2005_BFnrm1665_MOESM1_ESM.mov

S1 (movie) | Egg wounding in physiological Ca2+. A sea-urchin egg was immersed in artificial seawater containing 10 mM Ca2+ and FM1-43 dye, and was imaged confocally (10 second intervals between frames). Prior to wounding (first two frames), the membrane-impermeant, fluorescent FM1-43 dye labels the plasma membrane and some endosomal derivatives (cyoplasmic puncta). Shortly after wounding by laser irradiation (10 seconds; third frame), the labelling of internal membranes that have been exposed to the extracellular dye by the disruption can be observed. However, as can be seen by the examination of subsequent frames, a new surface boundary that restricts further dye influx had formed by the third frame. Indeed, this concave, new, delimiting membrane boundary is labelled in the third (and several subsequent frames) with FM1-43 dye. The egg successfully resealed an ~20-µm diameter disruption in less than 10 seconds (the limit of the temporal resolution in this experiment). Although, initially, this plasma membrane 'patch' has a concave profile, cytoskeletal remodelling will eventually restore the normal surface curvature at the disruption site. The initial stages of this reduction in concave curvature can be observed during the time course of this movie. (MOV 1721 kb)

41580_2005_BFnrm1665_MOESM2_ESM.mov

S2 (movie) | Egg wounding minus Ca2+. The same sea-urchin egg as was shown in Supplementary information S1 (movie) was immersed in artificial seawater containing no added Ca2+. The previous wound site is marked by intense fluorescence (FM1-43 staining of the discarded internal and plasma membranes). In the third frame (there is a 10 second interval between frames), a second laser wound of the same size as the first was made at the cellular pole opposite the first. In the remaining frames, extensive dye influx is observed, followed by a catastrophic spilling of the cytoplasmic contents into the medium. The egg was unable to reseal in the absence of physiological Ca2+. (MOV 1758 kb)

Related links

Related links

DATABASES

OMIM

Duchenne muscular dystrophy

limb-girdle muscular dystrophy

Prosite

C2 domain

Swiss-Prot

annexin A1

annexin A2

Bassoon

dysferlin

Myoferlin

otoferlin

Piccolo

SNAP25

synaptotagmin III

synaptotagmin VII

FURTHER INFORMATION

Tom Kirchhausen's laboratory

Rights and permissions

Reprints and permissions

About this article

Cite this article

McNeil, P., Kirchhausen, T. An emergency response team for membrane repair. Nat Rev Mol Cell Biol 6, 499–505 (2005). https://doi.org/10.1038/nrm1665

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1665

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing