SUMO2/3 conjugation of TDP-43 protects against aggregation
Summary
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 | Verde EM, Antoniani F, Mediani L, Secco V, Crotti S, Ferrara MC, Vinet J, Sergeeva A, Yan X, Hoege C, Stuani C, Paron F, Kao TT, Shrivastava R, Polanowska J, Bailly A, Rosa A, Aronica E, Goswami A, Shneider N, Hyman AA, Buratti E, Xirodimas D, Franzmann TM, Alberti S, Carra S |
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| Journal | Science advances |
| Publication Date | 2025 Feb 21;11(8):eadq2475 |
| PubMed | 39982984 |
| PubMed Central | PMC11844728 |
| DOI | 10.1126/sciadv.adq2475 |