Roles and regulation of secretory and lysosomal acid sphingomyelinase

Abstract

Acid sphingomyelinase occupies a prominent position in sphingolipid catabolism, catalyzing the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Enzymatic dysfunction of acid sphingomyelinase results in Niemann-Pick disease, a lysosomal storage disorder characterized at the cellular level by accumulation of sphingomyelin within the endo-lysosomal compartment. Over the past decade interest in the role of acid sphingomyelinase has moved beyond its ‘housekeeping’ function in constitutive turnover of sphingomyelin in the lysosome to include study of regulated ceramide generation. Ceramide functions as a bioactive sphingolipid with pleiotropic signaling properties, and has been implicated in diverse cellular processes of physiologic and pathophysiologic importance. Though many cellular enzymes have the capacity to generate ceramide, there is growing appreciation that ‘all ceramides are not created equal.’ Ceramides likely exert distinct effects in different cellular/subcellular compartments by virtue of access to other sphingolipid enzymes (e.g. ceramidases), effector molecules (e.g. ceramide-activated protein phosphatases), and neighboring lipids and proteins (e.g. cholesterol, ion channels). One of the unique features of acid sphingomyelinase is that it has been implicated in the hydrolysis of sphingomyelin in three different settings – the endo-lysosomal compartment, the outer leaflet of the plasma membrane, and lipoproteins. How a single gene product has the capacity to function in these diverse settings, and the subsequent impact on downstream ceramide-mediated biology is the subject of this review.

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

“…Ceramide is generated by (i) sphingomyelinases [30, 64, 65], (ii) by a de novo synthase pathway [30, 65], (iii) by a retrograde activity of the enzyme ceramidase that mediates the synthesis of ceramide from sphingosine [66], (iv) by the hydrolysis of complex glycosylated lipids [67] and (v) by hydrolysis of ceramide 1-phosphate [68]. Sphingomyelinases hydrolyse sphingomyelin to release ceramide.…”

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

“…2). These reactions take place within the plasma membrane (which can generate signaling sphingolipids) as well as in the lysosome, which is an important site of sphingolipid catabolism (Mao and Obeid 2008;Jenkins et al 2009;Schulze and Sandhoff 2011). Lysosomal ceramides and LCBs generated from breakdown of mature sphingolipids exit this organelle by poorly characterized means and return to the secretory pathway, where they can be recycled to form new sphingolipids.…”

“…Notable progress has been made in characterizing several sphingolipid catabolic enzymes (for a review, see Mao and Obeid 2008;Jenkins et al 2009). However, these studies have primarily focused on the roles of these enzymes in acute signaling responses rather than on their regulation in the context of sphingolipid homeostasis.…”

Regulated Secretion of Acid Sphingomyelinase

“…This resistance to cell death was attributable to lack of stress-induced Cer generation by the aSMase Ϫ/Ϫ cells, as exogenous Cer was capable of bypassing the metabolic block and inducing cell death (13). Subsequently, aSMase has been associated with a variety of physiologic and pathophysiologic cellular stress responses (14,15). However, despite continued interest in the roles and regulation of aSMase, some studies have questioned involvement of the aSMase/Cer pathway in cellular stress responses (16,17).…”