Regulation and function of neutral sphingomyelinase 2

Since the discovery of the first sphingolipids over a century ago, much progress has been made in the past 3 decades in understanding the biological significance of these bioactive molecules and the enzymes that regulate the synthesis and metabolism of the sphingolipid pathway. Neutral sphingomyelinase 2 (nSMase2) has emerged as a pivotal enzyme that generates ceramide by hydrolyzing sphingomyelin from the plasma membrane under cellular stress. In this review, we discuss structural and mechanistic studies, the upstream events leading to nSMases2 induction, and the downstream effects of increased nSMase2 activity that include roles of nSMase2 in the immune system, neurobiology, and cancer. Its roles in various diseases render the enzyme an attractive candidate as a drug target. We discuss new inhibitors of nSMase2 and their efficacy as well as limitations. Studies on Isc1, a homologue of the enzyme in yeast, continues to provide insights into its role in the control of cell cycle among many other biological functions, furthering our understanding of the significance of sphingolipids and the enzymes that modulate their levels in the cell.