{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T18:44:03Z","timestamp":1775933043796,"version":"3.50.1"},"posted":{"date-parts":[[2025,2,23]]},"group-title":"Cell Biology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T00:00:00Z","timestamp":1740268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,23]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>The midnolin-proteasome pathway degrades many nuclear proteins without ubiquitination, but how it operates mechanistically remains unclear. Here, we present structures of the midnolin-proteasome complex, revealing how established proteasomal components are repurposed to enable a unique form of proteolysis. While the proteasomal subunit PSMD2\/Rpn1 binds to ubiquitinated or ubiquitin-like proteins, we discover that it also interacts with the midnolin nuclear localization sequence, elucidating how midnolin\u2019s activity is confined to the nucleus. Likewise, PSMD14\/Rpn11, an enzyme that normally cleaves ubiquitin chains, surprisingly functions non-enzymatically as a receptor for the midnolin ubiquitin-like (Ubl) domain, positioning the substrate-binding Catch domain directly above the proteasomal entry site to guide substrates into the proteasome. Moreover, we demonstrate that midnolin downregulation is critical for the survival of myeloma cells by promoting the expression of its transcription factor substrate IRF4. Our findings uncover the mechanisms underlying the midnolin-proteasome pathway and midnolin downregulation as a driver of multiple myeloma.<\/jats:p>","DOI":"10.1101\/2025.02.22.639686","type":"posted-content","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T19:45:21Z","timestamp":1740339921000},"source":"Crossref","is-referenced-by-count":2,"title":["Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1705-5310","authenticated-orcid":false,"given":"Christopher","family":"Nardone","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA"},{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyuk-Soo","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Mintseris","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucy","family":"Ort","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew C. J.","family":"Yip","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milen","family":"Negasi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna K.","family":"Besschetnova","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Boston, MA, 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nolan","family":"Kamitaki","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven P.","family":"Gygi","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sirano","family":"Dhe-Paganon","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikhil","family":"Munshi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Boston, MA, 02215, USA"},{"name":"Veterans Affairs Boston Healthcare System, Boston, MA 02130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariateresa","family":"Fulciniti","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Boston, MA, 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael E.","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2679-5537","authenticated-orcid":false,"given":"Sichen","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA"},{"name":"Howard Hughes Medical Institute, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen J.","family":"Elledge","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Howard Hughes Medical Institute, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3393-6927","authenticated-orcid":false,"given":"Xin","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA"},{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA"},{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041110540875000_2025.02.22.639686v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3739"},{"key":"2026041110540875000_2025.02.22.639686v1.2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20191094"},{"key":"2026041110540875000_2025.02.22.639686v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-062917-011931"},{"key":"2026041110540875000_2025.02.22.639686v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80843-0"},{"key":"2026041110540875000_2025.02.22.639686v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.adh5021"},{"key":"2026041110540875000_2025.02.22.639686v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2016.05.013"},{"key":"2026041110540875000_2025.02.22.639686v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.10.013"},{"key":"2026041110540875000_2025.02.22.639686v1.8","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.253377"},{"key":"2026041110540875000_2025.02.22.639686v1.9","doi-asserted-by":"publisher","DOI":"10.3390\/cells8111373"},{"key":"2026041110540875000_2025.02.22.639686v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00341-1"},{"key":"2026041110540875000_2025.02.22.639686v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/ni1357"},{"key":"2026041110540875000_2025.02.22.639686v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nature07064"},{"key":"2026041110540875000_2025.02.22.639686v1.13","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00011.2023"},{"key":"2026041110540875000_2025.02.22.639686v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/ncb845"},{"key":"2026041110540875000_2025.02.22.639686v1.15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M404020200"},{"key":"2026041110540875000_2025.02.22.639686v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/nature06926"},{"key":"2026041110540875000_2025.02.22.639686v1.17","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad9421"},{"key":"2026041110540875000_2025.02.22.639686v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.03.004"},{"key":"2026041110540875000_2025.02.22.639686v1.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075898"},{"key":"2026041110540875000_2025.02.22.639686v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/nature01071"},{"key":"2026041110540875000_2025.02.22.639686v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2771"},{"key":"2026041110540875000_2025.02.22.639686v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2616"},{"key":"2026041110540875000_2025.02.22.639686v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.07.023"},{"key":"2026041110540875000_2025.02.22.639686v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav0725"},{"key":"2026041110540875000_2025.02.22.639686v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0736-4"},{"key":"2026041110540875000_2025.02.22.639686v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101052"},{"key":"2026041110540875000_2025.02.22.639686v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2016.05.018"},{"key":"2026041110540875000_2025.02.22.639686v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04671-8"},{"key":"2026041110540875000_2025.02.22.639686v1.29","doi-asserted-by":"publisher","DOI":"10.1101\/2021.10.04.463034"},{"key":"2026041110540875000_2025.02.22.639686v1.30","doi-asserted-by":"publisher","DOI":"10.1126\/science.abi6983"},{"key":"2026041110540875000_2025.02.22.639686v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/20367"},{"key":"2026041110540875000_2025.02.22.639686v1.32","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.131.6.1699"},{"key":"2026041110540875000_2025.02.22.639686v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90331-3"},{"key":"2026041110540875000_2025.02.22.639686v1.34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209037200"},{"key":"2026041110540875000_2025.02.22.639686v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"2026041110540875000_2025.02.22.639686v1.36","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160489"},{"key":"2026041110540875000_2025.02.22.639686v1.37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160462"},{"key":"2026041110540875000_2025.02.22.639686v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41559-020-01327-6"},{"key":"2026041110540875000_2025.02.22.639686v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"2026041110540875000_2025.02.22.639686v1.40","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-11-568881"},{"key":"2026041110540875000_2025.02.22.639686v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00550-x"},{"key":"2026041110540875000_2025.02.22.639686v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.010"},{"key":"2026041110540875000_2025.02.22.639686v1.43","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016892"},{"key":"2026041110540875000_2025.02.22.639686v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1100"},{"key":"2026041110540875000_2025.02.22.639686v1.45","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201947910"},{"key":"2026041110540875000_2025.02.22.639686v1.46","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20232132"},{"key":"2026041110540875000_2025.02.22.639686v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00529-7"},{"key":"2026041110540875000_2025.02.22.639686v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.12.013"},{"key":"2026041110540875000_2025.02.22.639686v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2005.07.007"},{"key":"2026041110540875000_2025.02.22.639686v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4169"},{"key":"2026041110540875000_2025.02.22.639686v1.51","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798319011471"},{"key":"2026041110540875000_2025.02.22.639686v1.52","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"2026041110540875000_2025.02.22.639686v1.53","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909047337"},{"key":"2026041110540875000_2025.02.22.639686v1.54","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889807021206"},{"key":"2026041110540875000_2025.02.22.639686v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1896"},{"key":"2026041110540875000_2025.02.22.639686v1.56","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792"},{"key":"2026041110540875000_2025.02.22.639686v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07215-4"},{"key":"2026041110540875000_2025.02.22.639686v1.58","doi-asserted-by":"publisher","DOI":"10.1021\/bi061994u"},{"key":"2026041110540875000_2025.02.22.639686v1.59","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1902931116"},{"key":"2026041110540875000_2025.02.22.639686v1.60","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.7b00913"},{"key":"2026041110540875000_2025.02.22.639686v1.61","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201200439"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.02.22.639686","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T17:54:18Z","timestamp":1775930058000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.02.22.639686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,23]]},"references-count":61,"URL":"https:\/\/doi.org\/10.1101\/2025.02.22.639686","relation":{},"subject":[],"published":{"date-parts":[[2025,2,23]]},"subtype":"preprint"}}