Acetylation of Axonal G3BP1 through ELP3 Accelerates Axon Regeneration

Dalla Costa, I.; Michenfelder, E.; Siciliano, S.; Tapita, A.; Buchanan, C. N.; Vaughn, L. S.; Lee, J.; Oses-Prieto, J. A.; Ma, C.; Thames, E.; Samra, N.; Ben-Dor, S.; Haffner-Krausz, R.; McElveen, M.; Smith, T. P.; Nawar, N.; Manaswiyoungkul, P.; Gunning, P. T.; Fainzilber, M.; Burlingame, A.; Zhu, H.; Perlson, E.; Sahoo, P. K.; Twiss, J. L.

doi:10.1101/2025.10.28.685144

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bioRxiv · 10.1101/2025.10.28.685144

Acetylation of Axonal G3BP1 through ELP3 Accelerates Axon Regeneration

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Abstract

Nerve injury triggers localized translation of axonal mRNAs to respond to injury and nerve regeneration. The core stress granule protein G3BP1 sequesters axonal mRNAs in granules before and after axotomy. G3BP1 granule disassembly can be regulated by post-translational modifications, including phosphorylation of S149 phosphorylation and acetylation of human K376 (mouse K374). Axonal G3BP1 undergoes phosphorylation after axotomy, but acetylation of G3BP1 in axons was unknown. Here we show that rodent G3BP1 undergoes K374 acetylation after axotomy is ELP3-dependent, which enhances axonal protein synthesis, accelerates nerve regeneration, and supports functional recovery. ELP3-depleted neurons exhibit reduced axon growth and increased axonal G3BP1 granules. The proximal axons degenerate rapidly despite maintaining soma connectivity, an effect prevented by expression of acetylmimetic G3BP1.Together, these findings identify G3BP1 acetylation via ELP3 as a critical regulator of both axonal regeneration and neuronal resilience, revealing a post-translational mechanism that links stress granule regulation to neuronal repair and protection.

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Dalla Costa, I., Michenfelder, E., Siciliano, S., Tapita, A., Buchanan, C. N., Vaughn, L. S., Lee, J., Oses-Prieto, J. A., Ma, C., Thames, E., Samra, N., Ben-Dor, S., Haffner-Krausz, R., McElveen, M., Smith, T. P., Nawar, N., Manaswiyoungkul, P., Gunning, P. T., Fainzilber, M., Burlingame, A., Zhu, H., Perlson, E., Sahoo, P. K., Twiss, J. L.. 2025-10-30. Acetylation of Axonal G3BP1 through ELP3 Accelerates Axon Regeneration. https://doi.org/10.1101/2025.10.28.685144

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