{"title":"Ubiquitin C-Terminal Hydrolase L1 (UCHL1), Beyond Hydrolysis.","authors":"Anwar Bdarneh, Inbal Maniv, Michael H Glickman","doi":"10.1002/bies.70028","DOIUrl":null,"url":null,"abstract":"<p><p>Ubiquitin C-terminal hydrolase L1 (UCHL1) is a component of the ubiquitin-proteasome system (UPS) linked to neurodegeneration. Despite its exceptionally high abundance in neurons, UCHL1's precise role remains unclear. This review critically examines the proposed functions of UCHL1 and the challenges to understanding its role in neuronal cells. While UCHL1 hydrolyzes small adducts from the C-terminus of ubiquitin, its occluded active site limits the range of possible substrates and restricts its activity as an efficient deubiquitinase (DUB). These constraints, alongside the paucity of identified substrates, challenge the centrality of this proposed role. We also explore the potential of UCHL1 acting as a ubiquitin ligase and its nonenzymatic role in stabilizing mono-ubiquitin by preventing its lysosomal degradation. By highlighting the unresolved complexities surrounding UCHL1, this perspective proposes several approaches to elucidate UCHL1's significance in the brain.</p>","PeriodicalId":9264,"journal":{"name":"BioEssays","volume":" ","pages":"e70028"},"PeriodicalIF":3.2000,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"BioEssays","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1002/bies.70028","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Ubiquitin C-terminal hydrolase L1 (UCHL1) is a component of the ubiquitin-proteasome system (UPS) linked to neurodegeneration. Despite its exceptionally high abundance in neurons, UCHL1's precise role remains unclear. This review critically examines the proposed functions of UCHL1 and the challenges to understanding its role in neuronal cells. While UCHL1 hydrolyzes small adducts from the C-terminus of ubiquitin, its occluded active site limits the range of possible substrates and restricts its activity as an efficient deubiquitinase (DUB). These constraints, alongside the paucity of identified substrates, challenge the centrality of this proposed role. We also explore the potential of UCHL1 acting as a ubiquitin ligase and its nonenzymatic role in stabilizing mono-ubiquitin by preventing its lysosomal degradation. By highlighting the unresolved complexities surrounding UCHL1, this perspective proposes several approaches to elucidate UCHL1's significance in the brain.
期刊介绍：
molecular – cellular – biomedical – physiology – translational research – systems - hypotheses encouraged
BioEssays is a peer-reviewed, review-and-discussion journal. Our aims are to publish novel insights, forward-looking reviews and commentaries in contemporary biology with a molecular, genetic, cellular, or physiological dimension, and serve as a discussion forum for new ideas in these areas. An additional goal is to encourage transdisciplinarity and integrative biology in the context of organismal studies, systems approaches, through to ecosystems, where appropriate.
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