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Post-translational modifications play major roles in the stability, function, and localization of target proteins involved in the nervous system. The ubiquitin-proteasome pathway uses small ubiquitin molecules to degrade neuronal proteins. Deubiquitinating enzymes (DUBs) reverse this degradation and thereby control neuronal cell fate, synaptic plasticity,axonal growth, and proper function of the nervous system.Moreover, mutations or downregulation of certain DUBshave been found in several neurodegenerative diseases, as well as gliomas and neuroblastomas. Based on emerging findings, DUBs represent an important target for therapeutic intervention in various neurological disorders. Here, we summarize advances in our understanding of the roles of DUBs related to neurobiology.
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http://dx.doi.org/10.14348/molcells.2020.2289 | DOI Listing |
Crit Care Explor
September 2025
Surgical Services, Minneapolis VA Medical Center, Minneapolis, MN.
Objective: This post hoc study of the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECT) III trial investigates whether improving traumatic brain injury (TBI) classification, using serum biomarkers (glial fibrillary acidic protein [GFAP] and ubiquitin carboxyl-terminal esterase L1 [UCH-L1]) and algorithmically assessed total lesion volume, could identify a subset of responders to progesterone treatment, beyond broad measures like the Glasgow Coma Scale (GCS) and Glasgow Outcome Scale-Extended (GOS-E), which may fail to capture subtle changes in TBI recovery.
Design: Brain lesion volumes on CT scans were quantified using Brain Lesion Analysis and Segmentation Tool for CT. Patients were classified into true-positive and true-negative groups based on an optimization scheme to determine a threshold that maximizes agreement between radiological assessment and objectively measured lesion volume.
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 PDFCell Chem Biol
September 2025
Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:
Deubiquitinating enzymes (DUBs) are crucial regulators of ubiquitin signaling and protein degradation that remain incompletely understood in part due to the lack of high-quality chemical probes. To address this challenge, we developed CAS-010, a low nanomolar, ubiquitin-competitive inhibitor of USP28 that demonstrates preferential activity against USP28 over other DUBs, while also exhibiting some activity against the closely related USP25. We rationalized our SAR trends and observed selectivity using a crystal structure of USP28 in complex with an inhibitor.
View Article and Find Full Text PDFmBio
September 2025
Microbiology and Cell Science Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, Florida, USA.
The rise of antibiotic-resistant bacterial pathogens poses a critical global health challenge, necessitating innovative therapeutic strategies. This study explores host-targeted therapies by focusing on deubiquitinating enzymes (DUBs), key regulators of the ubiquitin-proteasome system (UPS) that mediate host-pathogen interactions. Using -infected macrophages, we screened a UPS-targeted compound library and identified several compounds that enhanced bacterial clearance without affecting host cell viability.
View Article and Find Full Text PDFAutophagy
September 2025
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD) by activating CMA to counteract autophagy-dependent ferroptosis. Through sequencing analysis of human samples, we identified UCHL1 as a potential factor influencing disc degeneration.
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