Staying sane in the membrane: Neutral sphingomyelinase 2 as a master regulator of plasma membrane ceramide

Ceramide, a key signaling sphingolipid in the plasma membrane, plays a pivotal role in fundamental cellular processes such as adhesion, polarity, and programmed cell death. The generation of plasma membrane ceramide is largely attributed to the activity of two types of sphingomyelinases: neutral sphingomyelinase 2 (nSMase2, Smpd3) and acid sphingomyelinase (aSMase, Smpd1). While many studies have explored ceramide generation following experimental activation of these enzymes, the mechanisms governing basal or steady-state ceramide levels have remained poorly understood. Using an innovative mass spectrometry approach developed in the Canals’ lab, the team has quantified the distinct contributions of nSMase2 and aSMase to plasma membrane ceramide homeostasis. Remarkably, their findings reveal that nSMase2 is the primary driver of ceramide regulation in the plasma membrane, establishing its critical role in maintaining ceramide homeostasis and signaling under physiological conditions.