{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:32Z","timestamp":1792790372690,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,30]]},"group-title":"Cell Biology","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01AG11085"],"award-info":[{"award-number":["R01AG11085"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K99AG081456"],"award-info":[{"award-number":["K99AG081456"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Jane Coffin Childs Memorial Fund for Medical Research","id":[{"id":"https:\/\/ror.org\/04yhme281","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Academy of Medical Sciences","award":["SBF007\\100019"],"award-info":[{"award-number":["SBF007\\100019"]}],"id":[{"id":"https:\/\/ror.org\/00c489v88","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Isaac Newton Trust","id":[{"id":"https:\/\/ror.org\/02gn6ta77","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Cysteine residues are critical for both the catalytic activity and structural stability of many proteins, yet their high chemical reactivity threatens proteome integrity. Whether cells have specialized mechanisms to recognize and eliminate proteins with aberrant or exposed cysteines is unknown. By systematically analyzing the stability of thousands of cysteine-containing peptides, here we identify two complementary surveillance mechanisms targeting proteins with exposed cysteine residues. First, a set of E3 ubiquitin ligases \u2013 including AMBRA1, TRPC4AP, FBXO3, and FBXO21 \u2013 detects double cysteines and targets proteins for ubiquitin-dependent proteasomal degradation. Second, the PSMD14\/Rpn11 subunit of the 26S proteasome recognizes exposed cysteines in a ubiquitin-independent manner. Both pathways function in quality control to clear misfolded proteins exposing cysteine residues, including zinc finger-containing proteins. Mutational escape from the ubiquitin-independent pathway through dysregulation of ornithine decarboxylase or FOS levels is responsible for two human diseases, Bachmann-Bupp Syndrome and osteoblastoma, respectively. Our findings reveal conserved mechanisms for degrading proteins with exposed cysteines and uncover an alternative mode of substrate recognition by the 26S proteasome.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Short Summary<\/jats:title>\n                  <jats:p>Cysteine exposure acts as a conserved degradation signal that triggers two modes of turnover by the 26S proteasome: ubiquitin-dependent and direct, ubiquitin-independent degradation. These findings demonstrate the importance of maintaining cysteine homeostasis and reveal an alternative mode of proteasomal degradation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.29.755535","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:05:25Z","timestamp":1790787925000},"source":"Crossref","is-referenced-by-count":0,"title":["Proteasomal surveillance of exposed cysteines"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9980-9018","authenticated-orcid":false,"given":"Elijah L.","family":"Mena","sequence":"first","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA"},{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken C.","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Kairouz","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA"},{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Donovan","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa A.","family":"Soliman","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA"},{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Tsang","family":"Huang","sequence":"additional","affiliation":[{"name":"Broad Institute of Harvard and MIT, Cambridge, MA, USA"},{"name":"Department of Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bercin","family":"Yildiran","sequence":"additional","affiliation":[{"name":"Broad Institute of Harvard and MIT, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric S.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard I.","family":"Sherwood","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard T.","family":"Timms","sequence":"additional","affiliation":[{"name":"Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA"},{"name":"California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-6283","authenticated-orcid":false,"given":"Stephen J.","family":"Elledge","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA"},{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026102122350954000_2026.09.29.755535v2.1","doi-asserted-by":"publisher","DOI":"10.1021\/cr300163e"},{"key":"2026102122350954000_2026.09.29.755535v2.2","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.cell.2024.10.051","article-title":"Proteolethargy is a pathogenic mechanism in chronic disease","volume":"188","year":"2025","journal-title":"Cell"},{"key":"2026102122350954000_2026.09.29.755535v2.3","first-page":"1","article-title":"Signaling pathways of chronic kidney diseases, implications for therapeutics","volume":"7","year":"2022","journal-title":"Signal Transduct. 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