AI Article Synopsis
- After treating human platelets with thrombin, it was found that higher levels of USP15 and FKBP5 were expressed; manipulating USP15 levels affected FKBP5 stability and function.
- In experiments with mice lacking USP15 in their platelets, it was shown that this knockdown led to longer bleeding times and reduced thrombus formation, highlighting USP15's important role in regulating blood clotting.
Article Abstract
Background: Platelets have the hemostatic function, and their aberrant activation is associated with occlusive thrombus formation. Plasma exosomes are rich in platelets containing ubiquitin-specific peptidase 15 (USP15). Herein, we aim to explore the effect of USP15 on thrombosis, as well as expounding whether USP15 acts as an upstream target of FK506 binding protein 5 (FKBP5) to regulate occlusive thrombus formation.
Methods: Washed human platelets were treated with thrombin for measurement of USP15 and FKBP5 expressions. USP15 loss/gain-of-function variant in HEK293 cells was performed by cell transfection, and the interaction between USP15 and FKBP5 was examined using immunoprecipitation and ubiquitination assays. Mice with USP15-knockout platelets (Plt USP15) were modeled, and subjected to calculation of bleeding time, artery thrombosis imaging and clot retraction assay. FKBP5 expression and the inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE)/phosphatidylinositol 3-kinase (PI3K)/Rap1 pathway in wild-type and Plt USP15 mice-derived platelets were detected using Western blot. The activation of αIIbβ3 in washed platelets was analyzed using flow cytometry.
Results: USP15 and FKBP5 expressions were upregulated in platelets after thrombin treatment. Following transfection of USP15 knockdown and USP15 overexpression plasmids into HEK293 cells, FKBP5 protein expression was downregulated by USP15 knockdown while being upregulated by USP15 overexpression. USP15 bound to FKBP5 and protected FKBP5 against ubiquitination. Knockdown of platelet USP15 prolonged bleeding time, inhibited arterial thrombosis and delayed clot retraction in mice. Knockdown of platelet USP15 also decreased protein expressions of FKBP5, IKBKE and Rap1, p-PI3K/PI3K ratio, and activation of αIIbβ3 in mice.
Conclusion: USP15 knockdown in platelets affects thrombosis in mice by promoting the instability of FKBP5 to repress the activation of IKBKE/PI3K/Rap1 pathway-mediated αIIbβ3.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.31083/j.fbl2909325 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
N6-methyladenosine-modification of USP15 regulates chemotherapy resistance by inhibiting LGALS3 ubiquitin-mediated degradation via AKT/mTOR signaling activation pathway in hepatocellular carcinoma.
Cell Death Discov
January 2025
Department of Hepatobiliary Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China.
Hepatocellular carcinoma (HCC) is among the most malignant tumors and seriously threatens human health worldwide, and its incidence rate is increasing annually. USP15 is a member of the ubiquitination-specific protease (USP) family, which can regulate protein ubiquitination, thereby affecting their stability, and is dysregulated in many cancers, but its expression and regulatory mechanism in HCC are unclear. The aims of this study were to explore the role and mechanism of USP15 in regulating HCC cell stemness, proliferation, and lenvatinib resistance.
View Article and Find Full Text PDFHOXA3 activates USP15 to suppress autophagy and promote M2-type macrophage polarization in renal cell carcinoma via facilitating the deubiquitination of SQSTM1.
Am J Physiol Cell Physiol
December 2024
Department of Urology, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, P.R. China.
The disease burden of renal cell carcinoma (RCC) has decreased in recent years with advances in treatment, but its pathogeny still remains elusive. We aim to study the role of HOXA3/USP15/SQSTM1 axis on autophagy and M2-type macrophage polarization in RCC. In this study, cell apoptosis and proliferation were assessed by flow cytometry and CCK-8.
View Article and Find Full Text PDFTIFAB Modulates Metabolic Pathways in KMT2A::MLLT3-Induced AML Through HNF4A.
Blood Adv
December 2024
Case Western Reserve University, Cleveland, Ohio, United States.
Article Synopsis
- TIFAB (TRAF-interacting protein with forkhead-associated domain B) is an inhibitor of NF-kB signaling that plays significant roles in blood cell production and various blood cancers, including acute myeloid leukemia (AML).
- The study finds that deleting TIFAB in AML negatively affects leukemia stem/progenitor cell function, glucose consumption, and mitochondrial activity, while gene analysis shows reduced activity in key pathways such as MYC and glycolysis.
- HNF4A emerges as a crucial target of TIFAB, and restoring HNF4A levels can counteract the metabolic issues linked to TIFAB deficiency, emphasizing the importance of the TIFAB-HNF4A relationship in AML progression.
Ectopic USP15 expression inhibits HIV-1 transcription involving changes in YY1 deubiquitination and stability.
Front Cell Infect Microbiol
December 2024
Department of Microbiology and Immunology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL, United States.
Introduction: Protein homeostasis is maintained by the opposing action of ubiquitin ligase and deubiquitinase, two important components of the ubiquitin-proteasome pathway, and contributes to both normal physiological and pathophysiological processes. The current study aims to delineate the roles of ubiquitin-specific protease 15 (USP15), a member of the largest deubiquitinase family, in HIV-1 gene expression and replication.
Methods: We took advantage of highly selective and specific ubiquitin variants (UbV), which were recently designed and developed for USP15, and ascertained the inhibitory effects of USP15 on HIV-1 gene expression and production by transfection and Western blotting.
USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM.
Mol Med
November 2024
Suzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Background: Radiation-induced intestinal injury (RIII) interrupts the scheduled processes of abdominal and pelvic radiotherapy (RT) and compromises the quality of life of cancer survivors. However, the specific regulators and mechanisms underlying the effects of RIII remain unknown. The biological effects of RT are caused primarily by DNA damage, and ataxia telangiectasia mutated (ATM) is a core protein of the DNA damage response (DDR).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!