Down‐regulation of acid sphingomyelinase and neutral sphingomyelinase‐2 inversely determines the cellular resistance to plasmalemmal injury by pore‐forming toxins

What is it about?

Bacterial infectious diseases can lead to death or serious illnesses. These outcomes are largely the consequence of toxins, which are secreted by the bacteria and which are able to damage the plasma membranes of the host cells. Predominantly at risk are cells of the immune system. Fortunately however, the host cells can thwart these attacks by isolating the damaged membrane sites and expelling them in the form of microvesicles. These tiny particles then join the blood stream or the extracellular fluid and are later taken up for clearance by immune cells. We have investigated whether changes in the lipid composition of the plasma membrane influence the host cells' ability to repair their membrane. One of the major membrane lipids is sphingomyelin. We show here that enzymes, which regulate the stability of sphingomyelin (=sphingomyelinases) are critically involved in plasma membrane repair. Interestingly, this depends on the side of the plasma membrane on which the enzyme is active: if the activity of the enzyme (=acid sphingomyelinase) that works on the outer, extracellularly-oriented surface of the plasma membrane is reduced, the cells are unable to seal their membrane lesions; the amount of microvesicles is reduced and rapid cell death occurs. However, if the enzyme (=neutral sphingomyelinase) that acts on the inner, intracellular surface of the plasma membrane is reduced, the cells acquire an increased repair efficiency by secreting large amounts of microvesicles. Our results show that survival after bacterial toxin injury is not only dependent on the stability of sphingomyelin, but also that it is important on which side of the membrane this lipid is situated.

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