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Adv."],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:p>\n                    The 26\n                    <jats:italic toggle=\"yes\">S<\/jats:italic>\n                    proteasome engages with ubiquitinated substrates primarily through its constituent ubiquitin (Ub) receptors, which initiates a cascade of proteolytic processes. Leveraging this recognition mechanism, we developed a targeted protein degradation (TPD) strategy that recruits substrates directly to the proteasome, thereby bypassing the ubiquitination step. Our proteasome-targeting chimera, Protea-Tac, is a heterobifunctional protein degrader composed of a Ub receptor and an intracellular antibody. This chimera integrates into 26\n                    <jats:italic toggle=\"yes\">S<\/jats:italic>\n                    proteasomes without altering their structural or functional integrity. Protea-Tac with cognate antibodies degraded various target proteins, including c-Fos, BRD4,\n                    <jats:sup>Flag<\/jats:sup>\n                    TDP43,\n                    <jats:sup>HA<\/jats:sup>\n                    tau, and\n                    <jats:sup>GFP<\/jats:sup>\n                    ODC. We mechanistically demonstrated that this platform is (i) modular, allowing facile target switching, (ii) Ub independent, and (iii) highly target specific. Furthermore, Protea-Tac exhibited potent in vivo antitumor efficacy, posttranslationally inducing c-Fos degradation and substantially delaying tumor progression through both viral and nonviral delivery systems. These findings identify Protea-Tac as a distinct TPD platform capable of directly degrading intracellular proteins via engineered 26\n                    <jats:italic toggle=\"yes\">S<\/jats:italic>\n                    proteasomes.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh0227","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:04:04Z","timestamp":1789754644000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Ubiquitin receptor\u2013mediated, ubiquitin-independent targeted protein degradation via 26\n                    <i>S<\/i>\n                    proteasomes"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1185-9114","authenticated-orcid":true,"given":"Seh Hoon","family":"Park","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 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