Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization
Carpentier R, Kim J, Capizzi M, Kim H, Fäßler F, Hansen J, Kim MJ, Denarier E, Blot B, Degennaro M, Labou S, Arnal I, Marcaida MJ, Peraro MD, Kim D, Schur FK, Song J-J, Humbert S. 2025. Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization. Science Advances. 11(38), eadw4124.
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Author
Carpentier, Rémi;
Kim, Jaesung;
Capizzi, Mariacristina;
Kim, Hyeongju;
Fäßler, FlorianISTA 
;
Hansen, JesseISTA ;
Kim, Min Jeong;
Denarier, Eric;
Blot, Béatrice;
Degennaro, Marine;
Labou, Sophia;
Arnal, Isabelle
All
;
Hansen, JesseISTA ;
Kim, Min Jeong;
Denarier, Eric;
Blot, Béatrice;
Degennaro, Marine;
Labou, Sophia;
Arnal, Isabelle
All
Corresponding author has ISTA affiliation
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Abstract
The Huntingtin protein (HTT), named for its role in Huntington’s disease, has been best understood as a scaffolding protein that promotes vesicle transport by molecular motors along microtubules. Here, we show that HTT also interacts with the actin cytoskeleton, and its loss of function disturbs the morphology and function of the axonal growth cone. We demonstrate that HTT organizes F-actin into bundles. Cryo–electron tomography (cryo-ET) and subtomogram averaging (STA) structural analyses reveal that HTT’s N-terminal HEAT and Bridge domains wrap around F-actin, while the C-terminal HEAT domain is displaced; furthermore, HTT dimerizes via the N-HEAT domain to bridge parallel actin filaments separated by ~20 nanometers. Our study provides the structural basis for understanding how HTT interacts with and organizes the actin cytoskeleton.
Publishing Year
Date Published
2025-09-19
Journal Title
Science Advances
Publisher
American Association for the Advancement of Science
Acknowledgement
We thank C. Cuveillier, J. Delaroche, T. Ferraro, and A. Zanchi for help with TIRF experiments, electron microscopy preparation, data analysis, and cell cultures, respectively; A. Antkowiak, C. Bosc, C. Fassier, A. Fourest-Lieuvin, and V. Brandt for helpful discussions. We acknowledge the contribution of the Photonic Imaging Center of Grenoble Institute Neuroscience which is part of the ISdV core facility and certified by the IBiSA label and ICM.Quant (RRID:SCR_026393) core facility of the Paris Brain Institute (ICM); the AniRA lentivector production facility from the CELPHEDIA Infrastructure and SFR Biosciences (UAR3444/CNRS, US8/Inserm, ENS de Lyon, UCBL); the Scientific Service Units (SSUs) of ISTA through resources provided by Scientific Computing (SciComp, A. Schloegl and S. Elefante); and the Electron Microscopy Facility (EMF, V.V. Hodirnau). The software programs used for the processing were supported by SBGrid (www.sbgrid.org). This work was supported by the Agence Nationale pour la Recherche (AXYON: ANR-18-CE16-0009-01, S.H.), Austrian Science Fund (FWF) grants (P33367, F.K.M.S.; E435, J.M.H.), ChanZuckerberg Initiative (CZI) grant (DAF2021-234754, F.K.M.S.), Hereditary Disease Foundation Research Grant (HDF 990846, M.C.), European Union (ERC: ActinID 101076260, F.K.M.S.), Fondation pour la Recherche Médicale (FRM: équipe labellisée DEQ202203014675, S.H.; PhD fellowship, FDT202001010865, R.C.), Korea Health Industry Development Institute (KHIDI) (Korea-Switzerland global research support grant: RS-2023-00266300, J.-J.S.), National Research Foundation (NRF) of Korea (Korea-Austria collaborative grant NRF-2019K1A3A1A181160, J.-J.S. and F.K.M.S.; NRF-2020R1A2B5B03001517 and RS-2024-00333346 and RS-2024-00436173, J.-J.S.; 2021R1C1C1006700, D.K.).
Volume
11
Issue
38
Article Number
eadw4124
ISSN
IST-REx-ID
Cite this
Carpentier R, Kim J, Capizzi M, et al. Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization. Science Advances. 2025;11(38). doi:10.1126/sciadv.adw4124
Carpentier, R., Kim, J., Capizzi, M., Kim, H., Fäßler, F., Hansen, J., … Humbert, S. (2025). Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization. Science Advances. American Association for the Advancement of Science. https://doi.org/10.1126/sciadv.adw4124
Carpentier, Rémi, Jaesung Kim, Mariacristina Capizzi, Hyeongju Kim, Florian Fäßler, Jesse Hansen, Min Jeong Kim, et al. “Structure of the Huntingtin F-Actin Complex Reveals Its Role in Cytoskeleton Organization.” Science Advances. American Association for the Advancement of Science, 2025. https://doi.org/10.1126/sciadv.adw4124.
R. Carpentier et al., “Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization,” Science Advances, vol. 11, no. 38. American Association for the Advancement of Science, 2025.
Carpentier R, Kim J, Capizzi M, Kim H, Fäßler F, Hansen J, Kim MJ, Denarier E, Blot B, Degennaro M, Labou S, Arnal I, Marcaida MJ, Peraro MD, Kim D, Schur FK, Song J-J, Humbert S. 2025. Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization. Science Advances. 11(38), eadw4124.
Carpentier, Rémi, et al. “Structure of the Huntingtin F-Actin Complex Reveals Its Role in Cytoskeleton Organization.” Science Advances, vol. 11, no. 38, eadw4124, American Association for the Advancement of Science, 2025, doi:10.1126/sciadv.adw4124.
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