Curcumin Inhibits Membrane-Damaging Pore-Forming Function of the β-Barrel Pore-Forming Toxin Vibrio cholerae Cytolysin.

Mahendra Singh,N. Rupesh,Kausik Chattopadhyay,Shashi Bhushan Pandit

doi:10.3389/fmicb.2021.809782

Abstract

Vibrio cholerae cytolysin (VCC) is a β-barrel pore-forming toxin (β-PFT). Upon encountering the target cells, VCC forms heptameric β-barrel pores and permeabilizes the cell membranes. Structure-function mechanisms of VCC have been extensively studied in the past. However, the existence of any natural inhibitor for VCC has not been reported yet. In the present study, we show that curcumin can compromise the membrane-damaging activity of VCC. Curcumin is known to modulate a wide variety of biological processes and functions. However, the application of curcumin in the physiological scenario often gets limited due to its extremely poor solubility in the aqueous environment. Interestingly, we find that VCC can associate with the insoluble fraction of curcumin in the aqueous medium and thus gets separated from the solution phase. This, in turn, reduces the availability of VCC to attack the target membranes and thus blocks the membrane-damaging action of the toxin. We also observe that the soluble aqueous extract of curcumin, generated by the heat treatment, compromises the pore-forming activity of VCC. Interestingly, in the presence of such soluble extract of curcumin, VCC binds to the target membranes and forms the oligomeric assembly. However, such oligomers appear to be non-functional, devoid of the pore-forming activity. The ability of curcumin to bind to VCC and neutralize its membrane-damaging activity suggests that curcumin has the potential to act as an inhibitor of this potent bacterial β-PFT.

Highlights

Pore-forming toxins (PFTs) are the largest class of bacterial protein toxins (Dal Peraro and van der Goot, 2016)
Our result described above showed that the pore-forming activity of Vibrio cholerae cytolysin (VCC) against the target membranes was compromised in the presence of the soluble aqueous extract of curcumin in PBS
Our results suggest that curcumin can directly interact with VCC and can interfere with its membrane-damaging function

Summary

Introduction

Pore-forming toxins (PFTs) are the largest class of bacterial protein toxins (Dal Peraro and van der Goot, 2016). Upon binding to the target eukaryotic cells, bacterial PFTs form oligomeric pores in the membrane lipid bilayer that, in turn, damage the cell membranes and can eventually kill the target cells. Poreforming proteins (PFPs) and toxins are not restricted in the pathogenic bacteria only. These membrane-damaging proteins are documented in all the domains of life (Benton and BaylyJones, 2021). The membraneattack complex of the complement system and the perforin protein produced by the cytotoxic T-cells play critical roles in the induction of the immune functions (Liu and Lieberman, 2020; Spicer and Dunstone, 2021). PFTs and PFPs from the diverse kingdoms of life share very little or no similarity in their amino acid sequences, and they highlight enormous variations in their structures and mechanisms of actions (Mondal et al, 2020)

Methods

Results

Conclusion