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Both Ub-dependent and Ub-independent proteasome reporters accumulated when the concentration of mutant N-htt exceeded a solubility threshold, indicating that stabilization of 26S substrates is not linked to impaired Ub conjugation. Above this solubility threshold, mutant N-htt was rapidly recruited to cytoplasmic inclusions that were initially devoid of Ub. Although synthetically polyubiquitinated N-htt competed with other Ub conjugates for access to the proteasome, the vast majority of mutant N-htt in cells was not Ub conjugated. Our data confirm that proteasomes are not directly impaired by aggregated N-terminal fragments of htt; instead, our data suggest that Ub accumulation is linked to impaired function of the cellular proteostasis network.<\/jats:p>","DOI":"10.1083\/jcb.201110093","type":"journal-article","created":{"date-parts":[[2012,2,27]],"date-time":"2012-02-27T23:49:59Z","timestamp":1330386599000},"page":"573-587","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":164,"title":["Indirect inhibition of 26S proteasome activity in a cellular model of Huntington\u2019s disease"],"prefix":"10.1083","volume":"196","author":[{"given":"Mark S.","family":"Hipp","sequence":"first","affiliation":[{"name":"Department of Biology 1 , 2 , and 3"},{"name":"Biophysics Program 1 , 2 , and 3"},{"name":"Neurosciences Program, Stanford University, Stanford, CA 94305 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chetan N.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Biology 1 , 2 , and 3"},{"name":"Biophysics Program 1 , 2 , and 3"},{"name":"Neurosciences Program, Stanford University, Stanford, CA 94305 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirill","family":"Bersuker","sequence":"additional","affiliation":[{"name":"Department of Biology 1 , 2 , and 3"},{"name":"Biophysics Program 1 , 2 , and 3"},{"name":"Neurosciences Program, Stanford University, Stanford, CA 94305 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigit E.","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Biology 1 , 2 , and 3"},{"name":"Biophysics Program 1 , 2 , and 3"},{"name":"Neurosciences Program, Stanford University, Stanford, CA 94305 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen E.","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Department of Biology 1 , 2 , and 3"},{"name":"Biophysics Program 1 , 2 , and 3"},{"name":"Neurosciences Program, Stanford University, Stanford, CA 94305 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Shaler","sequence":"additional","affiliation":[{"name":"Stanford Research Institute International, Menlo Park, CA 94025 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Brandeis","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Alexsander Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron R.","family":"Kopito","sequence":"additional","affiliation":[{"name":"Department of Biology 1 , 2 , and 3"},{"name":"Biophysics Program 1 , 2 , and 3"},{"name":"Neurosciences Program, Stanford University, Stanford, CA 94305 1 , 2 , and 3"},{"name":"Department of Biology 1 , 2 , and 3"},{"name":"Biophysics Program 1 , 2 , and 3"},{"name":"Neurosciences Program, Stanford University, Stanford, CA 94305 1 , 2 , and 3"},{"name":"Department of Biology 1 , 2 , and 3"},{"name":"Biophysics Program 1 , 2 , and 3"},{"name":"Neurosciences Program, Stanford University, Stanford, CA 94305 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2012,2,27]]},"reference":[{"key":"2023072303151170000_bib1","doi-asserted-by":"publisher","first-page":"28253","DOI":"10.1074\/jbc.M109.004101","article-title":"Cytomegalovirus promoter up-regulation is the major cause of increased protein levels of unstable reporter proteins after treatment of living cells with proteasome inhibitors","volume":"284","author":"Alvarez-Castelao","year":"2009","journal-title":"J. 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