{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T11:41:26Z","timestamp":1786275686156,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,7]]},"group-title":"Cell Biology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"European Research Council","award":["ERC-2020-STG 947709"],"award-info":[{"award-number":["ERC-2020-STG 947709"]}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"crossref","award":["2380\/21"],"award-info":[{"award-number":["2380\/21"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"crossref","award":["3096\/21"],"award-info":[{"award-number":["3096\/21"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02xhk2825","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM156454"],"award-info":[{"award-number":["R35GM156454"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Protein homeostasis relies on protein quality control (PQC) pathways that survey the proteome to eliminate aberrant polypeptides. The BAG6 complex is a central PQC factor that recognizes exposed hydrophobic regions, a feature commonly associated with misfolded, mislocalized, and mistranslated proteins. Whether this surveillance machinery also regulates intact, functional proteins as part of physiological proteostasis has remained unclear. Using unbiased quantitative proteomics, we identify the ribosomal protein RPL22L1 as an endogenous BAG6 substrate whose abundance is controlled by continuous proteasomal degradation. This turnover requires the RNF115 E3 ligase activity but not the canonical BAG6 partner RNF126, defining RPL22L1 as a selective RNF115-dependent substrate. Mechanistically, we map a bipartite hydrophobic degron that distinguishes RPL22L1 from its stable paralog RPL22, and show that BAG6-RNF115-mediated degradation is governed by substrate assembly state. Accordingly, RPL22L1 is protected from degradation upon incorporation into the 60S ribosome, where it substitutes for RPL22. When RPL22 is lost, either genetically or through recurrent inactivating mutations in microsatellite-unstable cancers, the vacant ribosomal binding site permits RPL22L1 incorporation, protecting it from BAG6-mediated degradation. These findings establish unassembly-coupled degradation as a mechanism by which BAG6 regulates the abundance of functional protein components, ensuring that they accumulate only when incorporated into their native macromolecular complexes.<\/jats:p>","DOI":"10.64898\/2026.08.06.742952","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T13:15:12Z","timestamp":1786108512000},"source":"Crossref","is-referenced-by-count":0,"title":["BAG6-RNF115 Couples Protein Quality Control with Ribosome Assembly"],"prefix":"10.64898","author":[{"given":"Anat","family":"Raiff","sequence":"first","affiliation":[{"name":"The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Zenge","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alban","family":"Ordureau","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itay","family":"Koren","sequence":"additional","affiliation":[{"name":"The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080904001777000_2026.08.06.742952v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060310-170328"},{"key":"2026080904001777000_2026.08.06.742952v1.2","doi-asserted-by":"publisher","DOI":"10.3390\/biom11010060"},{"key":"2026080904001777000_2026.08.06.742952v1.3","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.chembiol.2021.04.008","article-title":"Ubiquitin ligases in cancer: Functions and clinical potentials","volume":"28","year":"2021","journal-title":"Cell Chem. 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