Following stimulation and release, the inactivated ASM is unable to contribute to ceramide generation at the outer leaflet of the membrane. The protonated compound interacts with the sapsonin domain of ASM, detaching them from the membrane, then undergoing proteolytic inactivation. On the right panel, the mode of action of cationic amphiphilic substances is illustrated: in an uncharged form at physiological pH value, the compounds diffuse across the cellular membrane through the cytoplasma into the lysosome, where the weak basic nitrogen atom of the compound is protonated because of the acid pH value of the lysosome. As a result, an increase in signaling quality and intensity is observed, controlling an adequate cellular response to external harmful stimuli. As a hallmark of ceramide-induced signal transduction, due to the trend for self-aggregation and formation of ceramide-enriched microdomains, subunits of receptor proteins are reorganized to functionally active receptor complexes such as TLR4, TNFR, etc. In the extracellular space, ASM mediates hydrolysis of SM (abundantly embedded into the outer leaflet of the membrane), generates ceramide, facilitating remodeling, and repair of the membrane (restoring integrity), as well as pathogen entry. Exposition of a cell membrane to external harmful stress events such as endogenous or exogenous stimuli (bacterial endotoxin, pro-inflammatory cytokines, pore-forming toxins, Table 2) is followed by intracellular Ca ++ influx, triggering the exocytosis of lysosomes, where ASM was bound to the inner lysosomal membrane by SAP domain. Release of acid sphingomyelinase (ASM) in the course of stress response and mode of action of its inhibition. Also, the potential role of lysosomotropic agents as functional inhibitors of this upstream alarming cascade is highlighted.įIASMA ceramide (CER) inhibitor organ failure (OF) sepsis sphingomyelinase (SMase). Here, we discuss the current state of the art on both the impact and function of the enzyme during host response and damage control.
As a consequence of cellular signaling, not only induction of cell death but also proliferation, differentiation, and fibrogenesis are affected. Its generation troubles the biophysical context of cellular membranes resulting in functional assembly and reorganization of proteins and receptors, also embedded in highly conserved response mechanisms. When secreted, acid sphingomyelinase (ASM) is able to hydrolyze sphingomyelin present at the outer leaflet of membranes to ceramide. How do one enzyme and one mediator manage all of these affairs? Under physiological conditions, the enzyme is located in the lysosomes and takes part in the noiseless metabolism of sphingolipids, but following stress the protein is secreted into circulation. Breakdown of the inert and constitutive membrane building block sphingomyelin to the highly active lipid mediator ceramide by extracellularly active acid sphingomyelinase is tightly regulated during stress response and opens the gate for invading pathogens, triggering the immune response, development of remote organ failure, and tissue repair following severe infection.