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Here, we have developed a robust and automated method to assess protein self-assembly in the cytoplasm using microtubules as nanoplatforms. Importantly, we have analyzed specifically the self-assembly of full-length TDP-43 and its mRNA binding that are regulated by the phosphorylation of its self-adhesive C-terminus, which is the recipient of many pathological mutations. We show that C-terminus phosphorylation prevents the recruitment of TDP-43 in mRNA-rich stress granules only under acute stress conditions because of a low affinity for mRNA but not under mild stress\u00a0conditions. In addition, the self-assembly of the C-terminus is negatively regulated by phosphorylation in the cytoplasm which in turn promotes TDP-43 nuclear import. We anticipate that reducing TDP-43 C-terminus self-assembly in the cytoplasm may be an interesting strategy to reverse TDP-43 nuclear depletion in neurodegenerative diseases.<\/jats:p>","DOI":"10.1038\/s42003-025-07456-7","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T10:56:35Z","timestamp":1738061795000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm"],"prefix":"10.1038","volume":"8","author":[{"given":"C\u00e9lia","family":"Rabhi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Babault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9n\u00e9dicte","family":"Desforges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Maucuer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7670-2146","authenticated-orcid":false,"given":"Serhii","family":"Pankivskyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitian","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Bollot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revital","family":"Rattenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3348-9514","authenticated-orcid":false,"given":"David","family":"Pastr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6492-1429","authenticated-orcid":false,"given":"Ahmed","family":"Bouhss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,28]]},"reference":[{"key":"7456_CR1","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1126\/science.1154584","volume":"319","author":"J Sreedharan","year":"2008","unstructured":"Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668\u20131672 (2008).","journal-title":"Science"},{"key":"7456_CR2","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1007\/s13311-015-0338-x","volume":"12","author":"EL Scotter","year":"2015","unstructured":"Scotter, E. L., Chen, H.-J. & Shaw, C. E. TDP-43 proteinopathy and ALS: insights into disease mechanisms and therapeutic targets. Neurotherapeutics 12, 352\u2013363 (2015).","journal-title":"Neurotherapeutics"},{"key":"7456_CR3","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202153632","volume":"22","author":"ZR Grese","year":"2021","unstructured":"Grese, Z. R. et al. Specific RNA interactions promote TDP\u201043 multivalent phase separation and maintain liquid properties. 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