{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T11:00:24Z","timestamp":1765969224355,"version":"3.48.0"},"reference-count":41,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2021_EKEA.122"],"award-info":[{"award-number":["2021_EKEA.122"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Pa 611\/11-1"],"award-info":[{"award-number":["Pa 611\/11-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Pa 611\/5-3"],"award-info":[{"award-number":["Pa 611\/5-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2016_Kolleg_15"],"award-info":[{"award-number":["2016_Kolleg_15"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Society of Internal Medicine"},{"name":"Medical Faculty Freiburg"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by the abnormal proliferation of myeloid cells. In addition to the main driver mutations in JAK2, MPL, and CALR, the transcription factor nuclear factor erythroid 2 (NFE2) has emerged as a key contributor to MPN pathophysiology. NFE2 expression is elevated in the majority of MPN patients, and augmented NFE2 activity in hematopoietic stem cells is sufficient to induce an MPN phenotype with spontaneous leukemic transformation in murine models. Moreover, NFE2 mutations, found in a subset of MPN patients, augment NFE2 activity and are associated with a markedly increased risk of progression to acute myeloid leukemia (AML). However, the molecular mechanism by which NFE2 mutations cause leukemogenesis is not understood. Here, we demonstrate that the E3 ubiquitin ligase ITCH mediates proteasomal degradation of wild-type (wt) NFE2 in HEK-293T cells. A gain-of-function truncation mutant, NFE2-226aa, retains the capacity to interact with ITCH but is no longer degraded. Rather, NFE2-226aa protects wt NFE2 from ITCH-dependent degradation, resulting in enhanced NFE2 activity.<\/jats:p>","DOI":"10.3390\/ijms262412112","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T15:41:12Z","timestamp":1765899672000},"page":"12112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NFE2 Truncation Mutants Protect Wild-Type NFE2 from ITCH-Dependent Degradation"],"prefix":"10.3390","volume":"26","author":[{"given":"Mirjam Elisabeth","family":"Hoeness","sequence":"first","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1984-6292","authenticated-orcid":false,"given":"Franziska","family":"Zell","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Titiksha","family":"Basu","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Gellrich","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Gr\u00fcnder","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1682-4487","authenticated-orcid":false,"given":"Jana","family":"Schulze","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"},{"name":"Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6100-0788","authenticated-orcid":false,"given":"Anja","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2915-3966","authenticated-orcid":false,"given":"Philipp","family":"Eble","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9919-7852","authenticated-orcid":false,"given":"Christoph","family":"Koellerer","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7977-0121","authenticated-orcid":false,"given":"Anne Marie","family":"Staehle","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarolta","family":"Bojtine Kovacs","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2857-2396","authenticated-orcid":false,"given":"Heike L.","family":"Pahl","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5082-0646","authenticated-orcid":false,"given":"Hans Felix","family":"Staehle","sequence":"additional","affiliation":[{"name":"Division of Molecular Hematology, Department of Medicine I, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/j.1365-2141.2005.05416.x","article-title":"Gene expression profiling in polycythaemia vera: Overexpression of transcription factor NF-E2","volume":"129","author":"Goerttler","year":"2005","journal-title":"Br. 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