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Cell–cell fusogens

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From Wikipedia, the free encyclopedia
(Redirected from Fusogen)
Cell–cell fusion
Identifiers
SymbolEFF-AFF
PfamPF14884
InterProIPR029213
Available protein structures:
PDB  IPR029213 PF14884 (ECOD; PDBsum)  
AlphaFold

Cell–cell fusogens are glycoproteins that facilitate the fusion of cell to cell membranes. Cell–cell fusion is critical for the merging of gamete genomes and the development of organs in multicellular organisms. Cell-cell fusion occurs when both actin cytoskeleton and fusogenic proteins properly rearrange across the cell membrane. This process is led by actin-propelled membrane protrusions.[1]

Identifiers

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Effects of EFF-1 and AFF-1 on vesicle morphology.

EFF-AFF are the identifiers for type 1 glycoproteins that makeup cell–cell fusogens. They were first identified when EFF-1 mutants were found to "block cell fusion in all epidermal and vulval epithelia" in the roundworm, Caenorhabditis elegans.[2] EFF-AFF is a family of type I membrane glycoproteins that act as cell–cell fusogens, named from ''Anchor cell fusion failure''. Because it was known that EFF-1 mutants successfully fused the anchor cell and (uterine seam) utse syncytium to produce a continuous uterine-vulval tube, where these connections failed, AFF-1 mutants were discovered. AFF-1 was deemed necessary for this process in addition to the fusion of heterologous cells in C. elegans.[3] The transmembrane forms of these proteins, like most viral fusogens, possess an N-terminal signal sequence followed by a long extracellular portion, a predicted transmembrane domain, and a short intracellular tail. " A striking conservation in the position and number of all 16 cysteines in the extracellular portion" of EFF-AFF proteins from different nematode species suggests that these proteins are folded in a similar 3D structure that is essential for their fusogenic activity.[4] C. elegans AFF-1 and EFF-1 proteins are essential for developmental cell-to-cell fusion and can merge insect cells. "Thus FFs comprise an ancient family of cellular fusogens that can promote fusion when expressed on a viral particle."[5]

Process

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Cell–cell fusogens are proteins that promote plasma membrane fusion among different cells. To be considered a fusogen, it must be required for fusion, fuse unfamiliar membranes, and be present on the fusing membrane when need be. These cells include but are not limited too: gametes, trophoblasts, epithelial, and other developmental cells. These fusogens mediate cell-cell fusion and can perform neuron repairs, auto-fusion, and sealing of the phagosomes. Although these proteins promote similar functions among cells, they have individual mechanisms. These are called unilateral (one fusing membrane needed to be present) and bilateral (same or different fusogens present at both membranes) mechanisms. Most fusogen mechanisms begin with hemifusion, but the mechanism for cell-cell fusogens consists of four separate steps.[6]

Step

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  1. Cells must identify and be near each other.
  2. Hemifusion occurs.
  3. Fusion pore in hemifusion structure opens, thus allowing for cell contents to merge.
  4. Cells completely join from pore expansion.

Applications

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Roles in gamete fertilization

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Cell–cell fusogens have several different applications. These chemical agents can play a significant part in sexual and asexual reproduction by promoting the fusion of the membrane bilayers.[6] With sexual reproduction, evidence found to prove that in mice, some mandatory sperm-egg fusogens are responsible for fusion; two particular proteins were IZUMO1 and CD9. After comparing the data of experiments done with plants, fungi, and invertebrates, it was seen that several crucial genes could have been responsible for fertilization. However, like yeasts, there were no genes found to be adequate for the fertilization process.[7] As of late, another protein has been classified as a gamete fusogen (HAP2 or GCS1). Like the previous example, this protein is present in plants, protists, and invertebrates. This fusogen resembles the eukaryotic somatic fusogen mentioned earlier, EFF-1. The presence of HAP2 induces hemifusion and the mixing of cell content.[6] Yet when considering asexual reproduction, somatic cells can also undergo cell-cell fusion or self-fusion. Two particular fusogens observed were SO and MAK-2. Evidence supports that these proteins control and regulate efficient protein concentration and localization.[7]

Roles in neuronal repair

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Chemical fusogens

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Although the EFF–AFF family consists of membrane proteins, the term fusogen is also used more broadly for non-protein agents that induce membrane fusion. Such chemical fusogens are not members of the EFF–AFF protein family. They can promote close membrane apposition or modify the repulsive forces between lipid bilayers, thereby facilitating their fusion.[8]

Polyethylene glycol (PEG) is an established chemical fusogen in cell biology. In hybridoma technology, PEG is commonly used to fuse antibody-producing B lymphocytes with immortal myeloma cells. The resulting hybridomas combine antibody secretion with sustained proliferation and are used to produce monoclonal antibodies.[9]

Roles in neuronal repair

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Axonal fusion is a repair process in which the proximal portion of a severed axon reconnects and fuses with its own separated distal fragment. It is therefore distinct from conventional cell–cell fusion between separate nucleated cells. In 2011, experiments in Caenorhabditis elegans demonstrated that regenerating mechanosensory axons could selectively fuse with their distal fragments, re-establishing membrane and cytoplasmic continuity and preventing Wallerian degeneration.[10] Subsequent work identified EFF-1 as the membrane fusogen involved in this regenerative process and showed that it acts with phosphatidylserine-recognition components of the apoptotic pathway.[11][12]

A separate experimental approach uses PEG to induce artificial fusion of severed axonal membranes. In 1986, George D. Bittner and colleagues reported that PEG treatment of transected crayfish giant axons restored axoplasmic continuity and transmission of action potentials across the lesion.[13] In 1990, Krause and Bittner reported rapid morphological fusion of the severed halves of an invertebrate myelinated axon following PEG application.[14]

Later experiments by Bittner's group in transected rat sciatic nerves reported rapid restoration of axonal and electrical continuity, attenuation of Wallerian degeneration, preservation of neuromuscular structures, and improved behavioral recovery.[15] A 2019 systematic review described the results of predominantly animal experiments as promising, but noted limited clinical evidence and unresolved technical parameters.[16]

PEG-based fusogens have also been investigated in experimental spinal cord injury. In 2026, Michael Lebenstein-Gumovski and colleagues reported an exploratory study of five pigs with complete thoracic spinal cord transection. Three animals receiving a PEG–chitosan sealant as part of a combined surgical, systemic PEG, and rehabilitation protocol were reported to regain the ability to stand and ambulate on all four limbs by 60 days, whereas two control animals remained paraplegic. The small group sizes and combined intervention prevented the effect of the fusogen from being evaluated independently of the other components of the protocol.[17]

A 2026 systematic review and meta-analysis, posted as a non-peer-reviewed bioRxiv preprint, surveyed 86 sources, with 20 studies included in its meta-analysis. It characterized the literature on chemical fusogens and neural repair as methodologically heterogeneous and in some cases inconsistent or contentious.[18] Thus, EFF-1 has a demonstrated role in natural axonal fusion in nematodes, and PEG is an established laboratory membrane-fusion agent, whereas therapeutic fusion of mammalian peripheral nerves and particularly the spinal cord remains experimental.

See also

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References

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  1. ↑ Shilagardi K, Li S, Luo F, Marikar F, Duan R, Jin P, et al. (April 2013). "Actin-propelled invasive membrane protrusions promote fusogenic protein engagement during cell-cell fusion". Science. 340 (6130): 359–63. Bibcode:2013Sci...340..359S. doi:10.1126/science.1234781. PMC 3631436. PMID 23470732.
  2. ↑ Mohler WA, Shemer G, del Campo JJ, Valansi C, Opoku-Serebuoh E, Scranton V, et al. (March 2002). "The type I membrane protein EFF-1 is essential for developmental cell fusion". Developmental Cell. 2 (3): 355–62. doi:10.1016/S1534-5807(02)00129-6. PMID 11879640.
  3. ↑ Sapir A, Choi J, Leikina E, Avinoam O, Valansi C, Chernomordik LV, et al. (May 2007). "AFF-1, a FOS-1-regulated fusogen, mediates fusion of the anchor cell in C. elegans". Developmental Cell. 12 (5): 683–98. doi:10.1016/j.devcel.2007.03.003. PMC 1975806. PMID 17488621.
  4. ↑ Sapir A, Avinoam O, Podbilewicz B, Chernomordik LV (January 2008). "Viral and developmental cell fusion mechanisms: conservation and divergence". Developmental Cell. 14 (1): 11–21. doi:10.1016/j.devcel.2007.12.008. PMC 3549671. PMID 18194649.
  5. ↑ Avinoam O, Fridman K, Valansi C, Abutbul I, Zeev-Ben-Mordehai T, Maurer UE, et al. (April 2011). "Conserved eukaryotic fusogens can fuse viral envelopes to cells". Science. 332 (6029): 589–92. Bibcode:2011Sci...332..589A. doi:10.1126/science.1202333. PMC 3084904. PMID 21436398.
  6. 1 2 3 Brukman NG, Uygur B, Podbilewicz B, Chernomordik LV (May 2019). "How cells fuse". The Journal of Cell Biology. 218 (5): 1436–1451. doi:10.1083/jcb.201901017. PMC 6504885. PMID 30936162.
  7. 1 2 Aguilar PS, Baylies MK, Fleissner A, Helming L, Inoue N, Podbilewicz B, et al. (July 2013). "Genetic basis of cell-cell fusion mechanisms". Trends in Genetics. 29 (7): 427–37. doi:10.1016/j.tig.2013.01.011. PMC 4022042. PMID 23453622.
  8. ↑ Abdou, Salma A.; Henderson, Peter W. (2019). "Fusogens: Chemical Agents That Can Rapidly Restore Function After Nerve Injury". Journal of Surgical Research. 233: 36–40. doi:10.1016/j.jss.2018.07.013. PMID 30502271.
  9. ↑ Mitra, Sanchita; Tomar, Pushpa Chaudhary (2021). "Hybridoma technology; advancements, clinical significance, and future aspects". Journal of Genetic Engineering and Biotechnology. 19 (1): 159. doi:10.1186/s43141-021-00264-6. PMC 8521504. PMID 34661773.
  10. ↑ Neumann B, Nguyen KC, Hall DH, Ben-Yakar A, Hilliard MA (2011). "Axonal regeneration proceeds through specific axonal fusion in transected C. elegans neurons". Developmental Dynamics. 240 (6): 1365–1372. doi:10.1002/dvdy.22606. PMC 3092806. PMID 21416556.
  11. ↑ Neumann B, Coakley S, Giordano-Santini R, Linton C, Lee ES, Nakagawa A, Xue D, Hilliard MA (2015). "EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway". Nature. 517 (7533): 219–222. doi:10.1038/nature14102. PMID 25567286.
  12. ↑ Neumann B, Linton C, Giordano-Santini R, Hilliard MA (2019). "Axonal fusion: An alternative and efficient mechanism of nerve repair". Progress in Neurobiology. 173: 88–101. doi:10.1016/j.pneurobio.2018.11.004. PMID 30500382.
  13. ↑ Bittner, George D.; Ballinger, Martis L.; Raymond, Mary A. (1986). "Reconnection of severed nerve axons with polyethylene glycol". Brain Research. 367 (1–2): 351–355. doi:10.1016/0006-8993(86)91617-3. PMID 3697710.
  14. ↑ Krause, T. L.; Bittner, George D. (1990). "Rapid morphological fusion of severed myelinated axons by polyethylene glycol". Proceedings of the National Academy of Sciences of the United States of America. 87 (4): 1471–1475. doi:10.1073/pnas.87.4.1471. PMC 53497. PMID 2304913.
  15. ↑ Mikesh M, Ghergherehchi CL, Hastings RL, Ali A, Rahesh S, Jagannath K, Sengelaub DR, Trevino RC, Jackson DM, Bittner GD (2018). "Polyethylene glycol solutions rapidly restore and maintain axonal continuity, neuromuscular structures, and behaviors lost after sciatic nerve transections in female rats". Journal of Neuroscience Research. 96 (7): 1223–1242. doi:10.1002/jnr.24225. PMC 5980706. PMID 29659058.
  16. ↑ Paskal AM, Paskal W, Pietruski P, Włodarski P (2019). "Polyethylene Glycol: The Future of Posttraumatic Nerve Repair? Systemic Review". International Journal of Molecular Sciences. 20 (6): 1478. doi:10.3390/ijms20061478. PMC 6471459. PMID 30909624.
  17. ↑ Lebenstein-Gumovski M, Rasueva T, Kovalev D, Canavero S, Zharchenko A, Petrov P, Zhirov A, Grin A (2026). "Fusogen-induced recovery of spinal cord function and morphology after complete transection". PLOS ONE. 21 (6) e0349579. doi:10.1371/journal.pone.0349579. PMC 13252762. PMID 42268810.
  18. ↑ Lebenstein-Gumovski, Michael; et al. (2026-03-23). "Fusogens for Axon Repair in Spinal Cord and Peripheral Nerve Injuries – Studies, Methods, and Mechanisms (systematic review with meta-analysis)". bioRxiv 10.64898/2026.03.20.712959v1.
This article incorporates text from the public domain Pfam and InterPro: IPR029213
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