was initially localized to the Golgi in several cell lines (Hofmann et al., 2000), subsequent studies have found localization of nSMase2 predominantly at the PM. Furthermore, this PM localization could be enhanced upon stimulation (e.g. TNF-α, H2O2) or in confluent cells (Clarke and Hannun, 2006; Clarke et al., 2007; Levy et al., 2006; Marchesini et al., 2004). Thus, the translocation of nSMase2 from the Golgi to the PM may be important for nSMase2 functions. Interestingly, nSMase2 has also been observed in the nucleus in human airway epithelial (HAE) cells using confocal microscopy (Levy et al., 2006). However, the mechanism underlying specific localization of nSMase2 and its potential trafficking between multiple subcellular locations is unclear and needs further elucidation. Finally, nSMase2 was reported to localize to the cytosolic leaflet of the PM, suggesting the presence of an inner leaflet pool of SM on the cytosolic face of the membranes (Tani and Hannun, 2007a). Notably, this is consistent with the enrichment of the nSMase2 activating lipid phosphatidylserine in the inner leaflet of the PM (Vance and Steenbergen, 2005).
