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Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation\u2013ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that SUMO\u2013ubiquitin networks protect cells from insoluble TDP-43 inclusions and propose the functionalization of PML as a potential future therapeutic avenue countering aggregation.<\/jats:p>","DOI":"10.1038\/s41589-025-01886-4","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T05:03:12Z","timestamp":1744866192000},"page":"1408-1419","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Induced proximity to PML protects TDP-43 from aggregation via SUMO\u2013ubiquitin networks"],"prefix":"10.1038","volume":"21","author":[{"given":"Kristina","family":"Wagner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9492-9413","authenticated-orcid":false,"given":"Jan","family":"Keiten-Schmitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9064-0356","authenticated-orcid":false,"given":"Bikash","family":"Adhikari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Upayan","family":"Patra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koraljka","family":"Husnjak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"McNicoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothee","family":"Dormann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"M\u00fcller-McNicoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Tascher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5299-6335","authenticated-orcid":false,"given":"Elmar","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8792-7700","authenticated-orcid":false,"given":"Stefan","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"1886_CR1","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41580-019-0101-y","volume":"20","author":"MS Hipp","year":"2019","unstructured":"Hipp, M. 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