The potent effect of mycolactone on lipid membranes

Milène Nitenberg (1) , Anaïs Benarouche (2) , Ofélia Maniti (1) , Estelle Marion (3) , Laurent L Marsollier (3) , Julie Géan (4) , Erick J Dufourc (4) , Jean-François Cavalier (2, 5) , Stéphane Canaan (2, 5) , Agnès P Girard-Egrot (1)

1 GEMBAS - Génie Enzymatique, Membrane Biomimétique et Assemblages Supramoléculaires
2 EIPL - Enzymologie interfaciale et de physiologie de la lipolyse
3 CRCINA-ÉQUIPE 6 - ATOMycA
4 CBMN - Chimie et Biologie des Membranes et des Nanoobjets
5 LISM - Laboratoire d'ingénierie des systèmes macromoléculaires

Mycolactone is a lipid-like endotoxin synthesized by an environmental human pathogen, Mycobacterium ulcerans, the causal agent of Buruli ulcer disease. Mycolactone has pleio-tropic 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. Mycolac-tone, 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 myco-lactone 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. Microdo-main 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, poten-tiating these effects.

Mots clés: Cell membranes; Lipids; Cholesterol; Toxins; Membrane proteins; Integral membrane proteins; Isotherms; Detergents

Domaines: Cancer

Milène Nitenberg, Anaïs Benarouche, Ofélia Maniti, Estelle Marion, Laurent L Marsollier, et al.. The potent effect of mycolactone on lipid membranes. PLoS Pathogens, 2018, 14 (1), pp.e1006814 (e-collection 2018 jan). ⟨10.1371/journal.ppat.1006814⟩. ⟨inserm-01709054⟩