The potent effect of mycolactone on lipid membranes

Abstract

Mycolactone is a lipid-like endotoxin synthesized by an environmental human pathogen, Mycobacterium ulcerans, the causal agent of Buruli ulcer disease. Mycolactone has pleiotropic effects on fundamental cellular processes (cell adhesion, cell death and inflammation). Various cellular targets of mycolactone have been identified and a literature survey revealed that most of these targets are membrane receptors residing in ordered plasma membrane nanodomains, within which their functionalities can be modulated. We investigated the capacity of mycolactone to interact with membranes, to evaluate its effects on membrane lipid organization following its diffusion across the cell membrane. We used Langmuir monolayers as a cell membrane model. Experiments were carried out with a lipid composition chosen to be as similar as possible to that of the plasma membrane. Mycolactone, which has surfactant properties, with an apparent saturation concentration of 1 μM, interacted with the membrane at very low concentrations (60 nM). The interaction of mycolactone with the membrane was mediated by the presence of cholesterol and, like detergents, mycolactone reshaped the membrane. In its monomeric form, this toxin modifies lipid segregation in the monolayer, strongly affecting the formation of ordered microdomains. These findings suggest that mycolactone disturbs lipid organization in the biological membranes it crosses, with potential effects on cell functions and signaling pathways. Microdomain remodeling may therefore underlie molecular events, accounting for the ability of mycolactone to attack multiple targets and providing new insight into a single unifying mechanism underlying the pleiotropic effects of this molecule. This membrane remodeling may act in synergy with the other known effects of mycolactone on its intracellular targets, potentiating these effects.

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

“…Fluorescently labelled mycolactones penetrated cultured fibroblasts in a non‐saturable and non‐competitive manner, compatible with passive diffusion across the plasma membrane, to localise in the cytosol [Chany et al., ; Guenin‐Mace et al., ; Snyder and Small, ]. According to recent studies using computer simulations or lipid monolayers [Lopez et al., ; Nitenberg et al., ], the passage of mycolactone across cellular membranes may nevertheless alter their dynamic properties, and cause mechanical and physical perturbations (see also section Mycolactone Perturbs the Lipid Bilayer ). Short‐term (4–16 h) exposure to mycolactone induced rapid alterations in the actin cytoskeleton of HeLa cells, coinciding with a defective capacity of the cells to establish adhesive contacts and migrate directionally in wound‐healing assays in vitro [Guenin‐Mace et al., ].…”

“…Mycolactone was originally isolated from acetone‐soluble lipids prepared from M. ulcerans , indicative of its lipophilic properties (George et al., ; see Figure ), and recent biophysical and computational studies confirm that mycolactone binds to a range of artificial phospholipid membranes [Lopez et al., ; Nitenberg et al., ]. Interestingly, the inclusion of cholesterol in these model systems promotes the insertion of mycolactone into the lipid phase leading to potential membrane destabilisation [Lopez et al., ; Nitenberg et al., ]. In the case of the cholesterol‐rich plasma membrane [Jacquemyn et al., ], these findings have clear implications for the mechanism by which mycolactone enters the cytosol and thereby accesses its intracellular targets, including the Sec61 complex.…”

“…In the case of the cholesterol‐rich plasma membrane [Jacquemyn et al., ], these findings have clear implications for the mechanism by which mycolactone enters the cytosol and thereby accesses its intracellular targets, including the Sec61 complex. Likewise, toxin‐induced changes to the plasma membrane bilayer [Lopez et al., ; Nitenberg et al., ] might contribute to its cellular effects. Cholesterol is inhibitory to co‐translocation protein translocation via the Sec61 complex [Kalies and Romisch, ], and hence its level in the ER membrane is comparatively low [Jacquemyn et al., ].…”

The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages

“…Several types of pathogenic mycobacteria apply this strategy to influence the fate of their host cells. For example, M. ulcerans produces the lipid-like endotoxin mycolactone which interacts with host membranes and disturbs their lipid organization 10 . In addition, pathogenic mycobacteria use lipoarabinomannan to enter neutrophils and prevent phagolysosome formation 11 .…”

Lipid Specificity of the Fusion of Bacterial Extracellular Vesicles with the Host Membrane

“…Additionally, our study also suggests that MV interaction with lipid rafts/phase boundaries may have an important role in altering host cell signalling (46). Very recently, Mycobacterium ulcerans endotoxin, Mycolactone, was shown to have potent effect on reorganization of raft-like model membranes (47). Likewise, Chlamydia pneumoniae effector protein CPn0678 was shown to induce curvature in the host membrane during its fusion (48).…”