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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Proteasome-associated cysteine deubiquitinases are molecular targets of environmental optical brightener compounds
Journal of cellular biochemistry, v 120(8), pp 14065-14075
01 Aug 2019
PMID: 30963630
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The levels of organic pollutants, such as optical brightener (OB) compounds, in the global environment have been increasing in recent years. The toxicological effects and signal transduction systems associated with OB toxicity have not been thoroughly studied. The ubiquitin-proteasome system (UPS) plays a crucial role in regulating multiple essential cellular processes, and proteasome-associated cysteine deubiquitinases (DUBs), ubiquitin C-terminal hydrolase L5 (UCHL5) and USP14, are two major regulators for (de)ubiquitination and stability of many important target proteins. Therefore, potential inhibition of UCHL5 and USP14 activities by some environmental chemicals might cause in vivo toxicity. In the current study we hypothesize that electrophilic OB compounds, such as 4,4 '-diamino-2,2 '-stilbenedisulfonic acid(DAST), fluorescent brightener 28 (FB-28) and FB-71, can interact with the catalytic triads (CYS, HIS, and ASP) of UCHL5 and USP14 and inhibit their enzymatic activities, leading to cell growth suppression. This hypothesis is supported by our findings presented in this study. Results from in silico computational docking and ubiquitin vinyl sulfone assay confirmed the UCHL5/USP14-inhibitory activities of these OB compounds that have potencies in an order of: FB-71 > FB-28 > DAST. Furthermore, inhibition of these two proteasomal DUBs by OBs resulted in cell growth inhibition and apoptosis induction in two human breast cancer cell models. In addition, we found that OB-mediated DUB inhibition triggers a feedback reaction in which expression of UCHL5 and USP14 proteins is increased to compromise the suppressed activities. Our study suggests that these commonly used OB compounds may target and inhibit proteasomal cysteine DUBs, which should contribute to their toxicological effects in vivo.
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Details
- Title
- Proteasome-associated cysteine deubiquitinases are molecular targets of environmental optical brightener compounds
- Creators
- Isel Castro - Wayne State UniversityElmira Ekinci - Wayne State UniversityXuemei Huang - Wayne State UniversityHassan Ali Cheaito - Wayne State UniversityYoung-Hoon Ahn - Wayne State UniversityJesus Olivero-Verbel - University of CartagenaQ. Ping Dou - Wayne State University
- Publication Details
- Journal of cellular biochemistry, v 120(8), pp 14065-14075
- Publisher
- Wiley
- Number of pages
- 11
- Grant note
- 647-2014 / COLCIENCIAS; Departamento Administrativo de Ciencia, Tecnologia e Innovacion Colciencias National Program for Doctoral Formation in Colombia P30CA022453 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R21CA184788; P30 CA022453 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Web of Science ID
- WOS:000471718300191
- Scopus ID
- 2-s2.0-85067297259
- Other Identifier
- 991020100204604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology