Sphingolipid Metabolism and Neutral Sphingomyelinases

Abstract

Sphingolipids are an important class of lipid molecules that play fundamental roles in our cells and body. Beyond a structural role, it is now clearly established that sphingolipids serve as bioactive signaling molecules to regulate diverse processes including inflammatory signaling, cell death, proliferation, and pain sensing. Sphingolipid metabolites have been implicated in the onset and progression of various diseases including cancer, lung disease, diabetes, and lysosomal storage disorders. Here we will review sphingolipid metabolism to introduce basic concepts as well as emerging complexities in sphingolipid function gained from modern technological advances and detailed cell and animal studies. Furthermore, we will discuss the family of neutral sphingomyelinases (N-SMases), which generate ceramide through the hydrolysis of sphingomyelin and are key enzymes in sphingolipid metabolism. Four mammalian N-SMase enzymes have now been identified. Most prominent is nSMase2 with established roles in bone mineralization, exosome formation, and cellular stress responses. Function for the other N-SMases have been more enigmatic and is an area of active investigation. The known properties and potential role(s) of each enzyme will be discussed to help guide to future studies.

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

“…Until recently, sphingolipids were considered structurally inert; however, they are now accepted to be fundamental signalling molecules, responsible for eliciting a wide range of signalling properties and cellular functions, encompassing roles in the regulation of cell growth, proliferation, differentiation, programmed death, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking. Current efforts are focused on deciphering the mechanisms underlying these varied roles, enabling a greater understanding of sphingolipid metabolism and lipid generation and action (Hannun & Obeid 2008, Merrill 2011, Airola & Hannun 2013; reviewed in Gault et al (2010)). …”

Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) Development

“…The core of a sphingolipid is an amino alcohol called sphingosine [18,19]. Complex sphingolipids located in the plasma membrane of cells (in particular nerve cells) have a structural function and are believed to protect the cell surface from harmful environmental factors and the regulation of inflammation, cell death, and cell proliferation involves sphingolipids [18].…”

Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation

“…However, how PS binding by the NTD activates the CAT of nSMase2 is unclear. The CAT is predicted to belong to the DNase I superfamily of enzymes (39), and the crystal structures of several bacterial homologs have been reported (40)(41)(42). However, all bacterial SMases derive from human pathogens, share limited sequence homology with nSMase2 (<10%), and contain a soluble unregulated CAT; these considerations have limited our understanding of nSMase2 regulation.…”