Proteasome‐associated cysteine deubiquitinases are molecular targets of environmental optical brightener compounds

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 proteasomeassociated 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/USP14inhibitory 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. K E Y W O R D S degradation, environmental pollutant, fluorescent brightening agent, molecular target, posttranslational modification

Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency

“…[49][50][51][52][53] The combined inhibition of both UCHL5 and USP14 results in lethality, indicates their nonredundancy, and suggests their role in maintaining cancer cell survival, which partly explains the finding that b-AP15, which selectively disrupts both USP14 and UCHL5 activity, was shown to significantly increase cancer cell apoptosis in vitro and to inhibit tumor progression, as well as exhibit robust antitumor activity. [54][55][56] Anti-cancer activity of IU1 is associated with growth arrest through inhibition of deubiquitilating activity of USP14, downregulation of COPS5, and upregulation of p53-dependent p21, p15, and beclin-1 and p53-independent COPS5 downstream effects AP-1, E2F1, p27, and cyclin E1, as well as induction of caspase-dependent apoptosis. Additionally, the effects of IU1 were shown to be independent of p53 status, as well as the expression of BCL-2, both of which can influence the response to bortezomib therapy.…”

Covalent polyester colouration by in situ chromophore creation

“…18 As white fabric ages it adopts a yellow shade that remains following laundering. [19][20][21] Attempts have been made to remedy this discolouration by the addition of trace quantities of blue dye, typically ultramarine blue. 19 In modern times, such agents have adopted the synonymous terms optical brighteners and fluorescent whitening agents, with their primary purpose being the absorption of ultraviolet (UV) light and the fluorescence of blue light.…”