SUMO2/3 conjugation of TDP-43 protects against aggregation
Cytosolic aggregation of the RNA binding protein TDP-43 (transactive response DNA-binding protein 43) is a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that during oxidative stress, TDP-43 becomes SUMO2/3-ylated by the SUMO E3 ligase protein PIAS4 (protein inhibitor of activated STAT 4) and enriches in cytoplasmic stress granules (SGs). Upon pharmacological inhibition of TDP-43 SUMO2/3-ylation or PIAS4 depletion, TDP-43 enrichment in SGs is accompanied by irreversible aggregation. In cells that are unable to assemble SGs, SUMO2/3-ylation of TDP-43 is strongly impaired, supporting the notion that SGs are compartments that promote TDP-43 SUMO2/3-ylation during oxidative stress. Binding of TDP-43 to UG-rich RNA antagonizes PIAS4-mediated SUMO2/3-ylation, while RNA dissociation promotes TDP-43 SUMO2/3-ylation. We conclude that SUMO2/3 protein conjugation is a cellular mechanism to stabilize cytosolic RNA-free TDP-43 against aggregation.
Authors
- Eleonora Aronica (ORCID: https://orcid.org/0000-0002-3542-3770)
- Anthony A. Hyman (ORCID: https://orcid.org/0000-0003-3664-154X)
- Simon Alberti (ORCID: https://orcid.org/0000-0003-4017-6505)
- Alessandro Rosa (ORCID: https://orcid.org/0000-0001-9999-7223)
- Valentina Secco
- Serena Carra (ORCID: https://orcid.org/0000-0003-0939-0140)
- Dimitris P. Xirodimas (ORCID: https://orcid.org/0000-0001-9275-1140)
- Tzu‐Ting Kao (ORCID: https://orcid.org/0009-0003-5529-7200)
- Jonathan Vinet (ORCID: https://orcid.org/0000-0001-9011-6207)
- Anand Goswami (ORCID: https://orcid.org/0000-0003-3294-5597)
- Emanuele Buratti (ORCID: https://orcid.org/0000-0002-1356-9074)
- Laura Mediani (ORCID: https://orcid.org/0000-0002-5870-1155)
- Francesca Paron
- Samuele Crotti (ORCID: https://orcid.org/0009-0009-5827-434X)
- Titus M. Franzmann (ORCID: https://orcid.org/0000-0002-4281-7209)
- Jolanta Polanowska (ORCID: https://orcid.org/0000-0001-7666-7010)
- Carsten Hoege
- Aleksandra Sergeeva (ORCID: https://orcid.org/0000-0003-0117-9076)
- Neil A. Shneider (ORCID: https://orcid.org/0000-0002-3223-7366)
- Francesco Antoniani (ORCID: https://orcid.org/0009-0003-7440-5633)
- Aymeric Bailly (ORCID: https://orcid.org/0000-0002-0842-5631)
- Cristiana Stuani
- Rohit Shrivastava (ORCID: https://orcid.org/0000-0001-7983-6510)
- Enza Maria Verde (ORCID: https://orcid.org/0009-0009-8688-7514)
- Xiao Yan (ORCID: https://orcid.org/0000-0002-2933-7702)
- Marc Ferrara (ORCID: https://orcid.org/0009-0001-8693-4466)
Institutions
- University of Modena and Reggio Emilia (IT)
- Centre National de la Recherche Scientifique (FR)
- Université de Montpellier (FR)
- Italian Institute of Technology (IT)
- Amsterdam Neuroscience (NL)
- Center for Nano Science and Technology (IT)
- Center for Systems Biology Dresden (DE)
- Amsterdam University Medical Centers (NL)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Columbia University (US)
- Technische Universität Dresden (DE)
- Sapienza University of Rome (IT)
- University of Amsterdam (NL)
- International Centre for Genetic Engineering and Biotechnology (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1126/sciadv.adq2475
- Citations
- 18
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 23.62