UCHL1

What is UCHL1 protein?

UCHL1 gene (ubiquitin C-terminal hydrolase L1) is a protein coding gene which situated on the short arm of chromosome 4 at locus 4p13. UCHL1, or ubiquitin C-terminal hydrolase L1, is a protein that is highly concentrated in the brain and spinal cord neurons. It is involved in the regulation of free ubiquitin levels within cells, protein degradation, and maintenance of the cellular redox state. UCHL1's dysfunction has been implicated in neurodegenerative diseases, and it is being explored as a potential therapeutic target for conditions such as Parkinson's disease. The UCHL1 protein is consisted of 223 amino acids and UCHL1 molecular weight is approximately 24.8 kDa.

What is the function of UCHL1 protein?

UCHL1 is a protein predominantly found in the brain and is associated with neurodegenerative diseases such as Parkinson's. It plays a role in the ubiquitin-proteasome system, which maintains cellular protein homeostasis by tagging damaged proteins for degradation. UCHL1 is also implicated in axonal health, and its dysfunction can lead to axonal degeneration and neuronal death.

Fig1. Potential mechanisms of UCHL1's structural and functional impairment in neurodegeneration. (Zhiping Mi, 2023)

UCHL1 related signaling pathway

UCHL1 plays a significant role in various signaling pathways related to neurodegenerative diseases and cancer. It functions as a deubiquitinating enzyme within the ubiquitin-proteasome system, targeting proteins for degradation or rescuing them from degradation, thereby impacting cellular processes like protein homeostasis, cell signaling, and the stress response. In the context of neurodegenerative diseases, UCHL1's dysfunction is associated with conditions like Parkinson's disease, where it may influence protein aggregation and clearance. In cancer, UCHL1 has been implicated in regulating pathways that control cell survival, proliferation, and metastasis. It may promote oncogenic transformation by stabilizing proteins like EGFR, influencing MAPK signaling, and regulating TGF-β pathway components such as TGFβR1 and SMAD2/3, which are crucial for cancer cell invasion and metastasis . These pathways make UCHL1 a potential therapeutic target for interventions in both neurodegenerative diseases and cancer.

UCHL1 related diseases

UCHL1 is prominently expressed in the brain and associated with neurodegenerative diseases such as Parkinson's. It is crucial for protein degradation via the ubiquitin-proteasome system, helping to clear damaged proteins and maintain cellular homeostasis. Dysregulation of UCHL1 is linked to neuronal cell death in conditions like Alzheimer's and traumatic brain injury. Moreover, UCHL1 has been identified as a potential biomarker for beta cell destruction in diabetes, indicating its relevance beyond neurodegenerative diseases.

Bioapplications of UCHL1

UCHL1 is a deubiquitinating enzyme predominantly found in the brain, playing a crucial role in axonal maintenance and neuronal integrity. It's implicated in neurodegenerative diseases like Parkinson's, and its dysregulation is linked to various cancers, promoting invasion and metastasis. UCHL1 has also been explored as a potential therapeutic target for conditions such as neurodegeneration and cancer. Moreover, it's used as a biomarker for the destruction of pancreatic beta cells in diabetes. Recent research has developed a specific small molecule inhibitor for UCHL1, which could be a valuable tool for studying its function and potential therapeutic applications.

Case Study 1: B Brackeva, 2015

This study explores the potential of plasma tests using label-free LC-MS/MS proteomics to detect beta cell destruction in type 1 diabetes, focusing on Ubiquitin COOH-terminal hydrolase 1 (UCHL1) as a candidate biomarker. UCHL1 was found to be highly expressed in rat and human beta cells and was validated in toxicity models. H2O2-induced necrosis in INS-1 cells and human islets led to a decrease in intracellular UCHL1 and its release into the extracellular space. In vivo, streptozotocin treatment caused a depletion of UCHL1 in islets, with a plasma UCHL1 increase detected before GAD65 in some animals. UCHL1 had a short half-life of 20 minutes in plasma and was rapidly cleared through the liver and spleen. Although UCHL1 shows promise as a biomarker for beta cell injury, its rapid elimination from plasma may limit its in vivo application.

Fig1. Toxin induces leakage of intracellular UCHL1 to the extracellular space in rat INS-1 cells.

Fig2. Clearance of non-labeled rhUCHL1 from plasma as measured by immunoassay.

Case Study 2: Shiqin Liu, 2024

Neuroendocrine carcinomas, like prostate cancer and small-cell lung cancer, often have a poor outlook and few treatment choices. Here UCHL1, a deubiquitinating enzyme, is increased in these cancer patients' tissues and plasma. When UCHL1 is reduced, it slows tumor growth and spread. It supports cancer progression by affecting proteins like POM121 and p53, and can be targeted with the inhibitor LDN-57444 to slow cancer growth and spread. Combining UCHL1 inhibitors with cisplatin, the typical treatment for these cancers, further delays tumor growth. This research uncovers UCHL1's role in cancer progression and its potential as a therapeutic target and biomarker for diagnosis and treatment monitoring in neuroendocrine carcinomas.

Fig3. POM121 and UCHL1 interaction was examined by PLA in situ assay.

Fig4. Ubiquitination of p53 upon overexpression of WT UCHL1(WT).

UCHL1 has several biochemical functions, for example, alpha-2A adrenergic receptor binding,cysteine-type endopeptidase activity,ligase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by UCHL1 itself. We selected most functions UCHL1 had, and list some proteins which have the same functions with UCHL1. You can find most of the proteins on our site.

UCHL1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with UCHL1 here. Most of them are supplied by our site. Hope this information will be useful for your research of UCHL1.

COPS5;EGFR;TERF2IP;CDKN1B;NCAM1;EIF1B;KRT4;MCC;VHL;EIF6;KRT17;IKBKE;CCDC14;ATG5;USP21