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Nuclear envelope (NE) blebs that contain FG-nucleoporins (FG-Nups) and K48-linked ubiquitin are the hallmark phenotype of Torsin manipulation across disease models of DYT1 dystonia. While the aberrant deposition of FG-Nups is caused by defective nuclear pore complex assembly, the source of K48-ubiquitylated proteins inside NE blebs is not known. Here, we demonstrate that the characteristic K48-ubiquitin accumulation inside blebs requires p97 activity. This activity is highly dependent on the p97 adaptor UBXD1. We show that p97 does not significantly depend on the Ufd1\/Npl4 heterodimer to generate the K48-ubiquitylated proteins inside blebs, nor does inhibiting translation affect the ubiquitin sequestration in blebs. However, stimulating global ubiquitylation by heat shock greatly increases the amount of K48-ubiquitin sequestered inside blebs. These results suggest that blebs have an extraordinarily high capacity for sequestering ubiquitylated protein generated in a p97-dependent manner. The p97\/UBXD1 axis is thus a major factor contributing to cellular DYT1 dystonia pathology and its modulation represents an unexplored potential for therapeutic development.<\/jats:p>","DOI":"10.3390\/ijms23094627","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T05:07:22Z","timestamp":1650604042000},"page":"4627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["p97\/UBXD1 Generate Ubiquitylated Proteins That Are Sequestered into Nuclear Envelope Herniations in Torsin-Deficient Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Sarah M.","family":"Prophet","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte S.","family":"Naughton","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1237-4267","authenticated-orcid":false,"given":"Christian","family":"Schlieker","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA"},{"name":"Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.neuron.2005.11.010","article-title":"Loss of the dystonia-associated protein torsina selectively disrupts the neuronal nuclear envelope","volume":"48","author":"Goodchild","year":"2005","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/ng0997-40","article-title":"The early-onset torsion dystonia gene (dyt1) encodes an atp-binding protein","volume":"17","author":"Ozelius","year":"1997","journal-title":"Nat. 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