{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T17:34:48Z","timestamp":1767202488284,"version":"3.48.0"},"reference-count":59,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institutes of Health\/NIGMS","doi-asserted-by":"publisher","award":["R01GM151447"],"award-info":[{"award-number":["R01GM151447"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Accumulation of misfolded proteins is implicated in neurodegenerative diseases. One of these is Huntington\u2019s disease, which is caused by an expansion of trinucleotide (CAG) repeats in exon 1 of huntingtin gene (HTT). This expansion results in the production of mutant huntingtin exon1 protein (mHttEx1) containing polyglutamine tracks that is prone to cytotoxic aggregation. These mHttEx1 aggregates range from small soluble aggregates to large insoluble inclusion bodies. The mechanisms to clear mHttEx1 aggregates include ubiquitin-dependent proteasomal degradation and autophagy. For the proteasomal degradation of mHttEx1, ubiquitinated protein is first recognized by the Cdc48 complex for extraction and unfolding. For autophagy, mHttEx1 inclusion bodies are engulfed by an autophagosome, which fuses with the vacuole\/lysosome and delivers cargo for vacuolar degradation. We name this autophagy IBophagy. In this study, we further show that the ubiquitination of mHttEx1 by the E3 ligase San1, its extraction and unfolding by the Cdc48 complex, and subsequent proteasomal degradation are all essential steps for mHttEx1 IBophagy in budding yeast, revealing a new layer of autophagy regulation and mHttEx1 cytotoxicity.<\/jats:p>","DOI":"10.3390\/cells15010068","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T17:24:58Z","timestamp":1767201898000},"page":"68","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteasomal Degradation of Mutant Huntingtin Exon1 Regulates Autophagy"],"prefix":"10.3390","volume":"15","author":[{"given":"Austin","family":"Folger","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306-4300, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuan","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Biological Sciences, Hebei University, Baoding 071002, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phasin","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306-4300, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7028-4526","authenticated-orcid":false,"given":"Sophia L.","family":"Owutey","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306-4300, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6782-0570","authenticated-orcid":false,"given":"Yanchang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306-4300, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nrm2993","article-title":"Cellular strategies for controlling protein aggregation","volume":"11","author":"Tyedmers","year":"2010","journal-title":"Nat. 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