Dysregulation of the Ubiquitin-Proteasome System by Curcumin Suppresses Coxsackievirus B3 Replication

Abstract

Curcumin (diferuloylmethane), a natural polyphenolic compound extracted from the spice turmeric, has been reported to have anti-inflammatory, antioxidant, and antiproliferative properties by modulating multiple cellular machineries. It inhibits several intracellular signaling pathways, including the mitogen-activated protein kinases (MAPKs), casein kinase II (CKII), and the COP9 signalosome (CSN), in various cell types. It has also been recently demonstrated that exposure to curcumin leads to the dysregulation of the ubiquitinproteasome system (UPS). Coxsackievirus infection is associated with various diseases, including myocarditis and dilated cardiomyopathy. In searching for new antiviral agents against coxsackievirus, we found that treatment with curcumin significantly reduced viral RNA expression, protein synthesis, and virus titer and protected cells from virus-induced cytopathic effect and apoptosis. We further demonstrated that reduction of viral infection by curcumin was unlikely due to inhibition of CVB3 binding to its receptors or CVB3-induced activation of MAPKs. Moreover, gene silencing of CKII and Jab1, a component of CSN, by small interfering RNAs did not inhibit the replication of coxsackievirus, suggesting that the antiviral action of curcumin is independent of these pathways. Finally, we showed that curcumin treatment reduced both the 20S proteasome proteolytic activities and the cellular deubiquitinating activities, leading to increased accumulation of ubiquitinated proteins and decreased protein levels of free ubiquitin. We have recently demonstrated that the UPS-mediated protein degradation and/or modification plays a critical role in the regulation of coxsackievirus replication. Thus, our results suggest an important antiviral effect of curcumin wherein it potently inhibits coxsackievirus replication through dysregulation of the UPS.

Curcumin induces apoptosis-independent death in oesophageal cancer cells

“…Cytotoxicity correlated with the ability of curcumin to elevate the levels of poly-ubiquitinated proteins and to accumulate the mitotic regulator cyclin B1. This is consistent with evidence that curcumin can influence multiple targets because of its inhibitory effects on the ubiquitin -proteasome system (UPS) (Jana et al, 2004;Si et al, 2007).…”

“…The primary target of curcumin is unknown; however, an emerging body of evidence suggests that this compound may achieve its diverse effects through inhibition of the UPS (Henke et al, 1999;Uhle et al, 2003;Jana et al, 2004;Si et al, 2007). We therefore looked for evidence of the accumulation of polyubiquitinated proteins after treatment.…”

Curcumin Sensitizes Acute Promyelocytic Leukemia Cells to Unfolded Protein Response–Induced Apoptosis by Blocking the Loss of Misfolded N-CoR Protein

“…As curcumin is also known to be a potent inhibitor of proteasomal activity (20)(21)(22), we tested whether curcumin-induced stabilization of N-CoR protein was a result of an inhibition of cellular proteasomal activity. Effect of curcumin on the proteasomal activity of 293T cells was tested using the proteasome sensor pZsProSensor-1, which consists of the mouse ornithine decarboxylase degradation domain (MODC d410) fused to green florescent protein (GFP) ZsGreen.…”

Structure–activity relationship analysis of curcumin analogues on anti‐influenza virus activity

“…Furthermore, a number of studies indicate curcumin (Cur) is a potent antiviral agent as a result of its ability to interfere with the cellular signalling pathways or with proteins required for viral replication [4][5][6][7][8].…”