Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Polyubiquitin chain diversity generates a 'ubiquitin code' that universally regulates protein abundance, localization, and function. Functions of polyubiquitin diversity are mostly unknown, with lack of progress due to an inability to selectively tune protein polyubiquitin linkages in live cells. We develop linkage-selective engineered deubiquitinases (enDUBs) by fusing linkage-selective DUB catalytic domains to GFP-targeted nanobody and use them to investigate polyubiquitin linkage regulation of an ion channel, YFP-KCNQ1. YFP-KCNQ1 in HEK293 cells has polyubiquitin chains with K48/K63 linkages dominant. EnDUBs yield unique effects on channel surface abundance with a pattern indicating: K11 promotes ER retention/degradation, enhances endocytosis, and reduces recycling; K29/K33 promotes ER retention/degradation; K63 enhances endocytosis and reduces recycling; and K48 is necessary for forward trafficking. EnDUB effects differ in cardiomyocytes and on KCNQ1 disease mutants, emphasizing ubiquitin code mutability. The results reveal distinct polyubiquitin chains control different aspects of KCNQ1 abundance and subcellular localization and introduce linkage-selective enDUBs as potent tools to demystify the polyubiquitin code.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218124 | PMC |
| http://dx.doi.org/10.1038/s41467-025-60893-0 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Ubiquitin-specific protease 7 promotes the growth and oncogenic potential of acute myeloid leukemia cells through the deubiquitination and upregulation of LRRK2.
J Biol Chem
September 2025
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Korea. Electronic address:
Leucine-rich repeat kinase 2 (LRRK2), a large protein with kinase and GTPase activities, regulates various cellular pathways, including autophagy, endocytosis, and mitochondrial dynamics. LRRK2, extensively studied in the context of Parkinson's disease, is functionally impaired in other pathological conditions as well, including inflammatory bowel disease, cancer, and cardiovascular diseases. Despite its critical functions, the mechanisms controlling LRRK2 protein stability are not fully understood.
View Article and Find Full Text PDFDeubiquitinase JOSD2 promotes acute pancreatitis by removing K63-linked poly-ubiqutin chain on PCNA in pancreatic acinar cells.
Cell Mol Gastroenterol Hepatol
September 2025
Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China. Electronic address:
Background & Aims: Acute pancreatitis (AP) results in localized pancreatic injury or systemic inflammatory responses, contributing to high morbidity and mortality worldwide. Acinar cell death and inflammation are critical key drivers of AP progression. Some deubiquitinases (DUBs), which regulate the stability and/or activity of substrate proteins, may play a role in the development of AP.
View Article and Find Full Text PDFUbiquitinome profiling identifies USP13-CMAS axis as critical regulator of hair follicular melanogenesis via K48-linked polyubiquitination.
Cell Signal
August 2025
College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, Jiangsu, China. Electronic address:
The ubiquitin-proteasome system critically regulates melanogenesis through post-translational modifications. However, the specific deubiquitination substrates involved in this regulation remain poorly characterized. This study employed multi-omics integration and functional validation to decipher the role of USP13 in melanocyte (MC) biology.
View Article and Find Full Text PDF[Evaluation of high-throughput detection technology for ubiquitination signals based on ThUBD].
Sheng Wu Gong Cheng Xue Bao
August 2025
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, College of Chemistry and Materials Science, Hebei University, Baoding 071002, Hebei, China.
Ubiquitination is one of the most widely distributed, structurally diverse, and functionally important post-translational modifications for proteins in eukaryotic cells. At present, the methods for detecting ubiquitination signals mainly include immunological detection based on specific antibodies, mass spectrometry, and detection based on ubiquitin-binding domain (UBD), which together constitute a tool library for studying ubiquitination signals. Our team has previously developed a high-throughput detection technology based on an artificial tandem hybrid ubiquitin-binding domain (ThUBD), which achieves universal and highly sensitive detection of all polyubiquitin chain modification signals.
View Article and Find Full Text PDFHighly specific intracellular ubiquitination of a small molecule.
Nat Chem Biol
August 2025
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Ubiquitin is a small, highly conserved protein that acts as a posttranslational modification in eukaryotes. Ubiquitination of proteins frequently serves as a degradation signal, marking them for disposal by the proteasome. Here we report a novel small molecule from a diversity-oriented synthesis library, BRD1732, that is directly ubiquitinated in cells, resulting in dramatic accumulation of inactive ubiquitin monomers and polyubiquitin chains, which causes broad inhibition of the ubiquitin-proteasome system.
View Article and Find Full Text PDF