ABSTRACT
Activation- Induced SM Breakdown and Ceramide Generation ................... 138 7.4.1 Acid Sphingomyelinase .................................................................... 138 7.4.2 Neutral Sphingomyelinase ................................................................ 141
7.5 Characteristics of Ceramide-Enriched Domains and Functional Consequences ...................................................................... 141 7.5.1 Consequences of Biophysical Alterations Relating
to Ceramide Accumulation ............................................................... 142 7.5.1.1 Ceramides in Regulating Membrane Curvature,
Vesiculation, and Phagocytosis .......................................... 142 7.5.1.2 Ceramides in Membrane Fusion ........................................ 144
7.5.2 Proteins Associating with SM-or Ceramide-Enriched Membrane Domains ......................................................................... 144
7.5.3 The Ceramide-Enriched Polarity Complex ...................................... 146 7.5.4 Transbilayer Communication Promotes Interaction of Cytosolic
Proteins with SL-Enriched Membrane Domains ............................. 146 7.6 SM/Ceramide-Enriched Platforms as Sites of Downstream
Effector Regulation ....................................................................................... 147 7.6.1 Regulation of Akt Kinase Activity ................................................... 148 7.6.2 ERM Proteins and Actin Cytoskeleton ............................................ 148 7.6.3 Downstream Effectors: Transcription Factors .................................. 150
7.7 Biological Consequences of SM Breakdown and Ceramide Accumulation: Role in Pathogen Uptake, Release, and Host Defenses........ 151 7.7.1 Pathogen Uptake ............................................................................... 151
7.7.1.1 Bacterial/Parasite Internalization and Induction of Host Cell Death ............................................................. 151
7.7.1.2 Viral Uptake ....................................................................... 152
Regardless as to whether they accumulate owing to de novo synthesis or subsequent to sphingomyelin (SM) breakdown, ceramides are membrane constituents that (1) biochemically, (2) biophysically, and (3) functionally strongly affect membrane activity. They do so (1) in serving as central hubs in the sphingolipid (SL) metabolism as they represent central building blocks for complex glycosylated SL (glycosphingolipids, or GSLs), as well as precursors for biologically active metabolites; (2) in altering membrane uidity and rigidity, thereby promoting dynamics of inward/outward curvature and vesiculation; and (3) by compartmentalizing and segregating membrane proteins and lipids, thereby acting as organizers of signal perception and propagation. Their activity is conned to membranes. Therefore, they are no classical second messengers. Because of their multifunctional properties, their biological activities range from conveying apoptotic stimuli to affecting cell differentiation, adhesion, migration, cell-cell communication, and endo/phagocytosis, as well as pathogen interactions especially in uptake and release. Ceramide derivatives, which are permanently generated along with ceramide accumulation under rheostat and activated conditions, are bioactive lipids as well and do inuence or exert biological processes. This has been documented in numerous studies describing biological activities of ceramide metabolites that are not dealt with within this chapter. As a recent example, the neutral sphingomyelinase (NSM) activity associated with a mitochondrial proximal compartment has been found required for lowering the threshold for BAX and BAK activation in mitochondrial apoptosis. However, cooperation between these proteins relied on the ceramide metabolites sphingosine-1phosphate (S1P) and hexadecenal rather than ceramide itself.1 For the sake of clarity and to meet the topic, we will focus on effects directly associated with the activity of sphingomyelinases and ceramides. What should, however, also be made initially clear is that ceramide-enriched domains may not be considered as nanodomains. This is because, when generated in response to SM breakdown, they fuse into large domains that range between a few hundred nanometers to micrometers and are easily visible by standard confocal microscopy.
