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The non-lysosomal β-glucosylceramidase GBA2 (EC3.2.1.45, GH116) is ubiquitously expressed in various mammal tissues and cell types where it catalyzes the hydrolysis of glucosylceramide into glucose and ceramide. Although it has been known for many years that the central nervous system is the main site of GBA2 expression and activity, little information has been available so far on the role of this protein in the neuronal development, senescence and homeostasis. In the present review, we summarize the state-of-the art of this enzyme and in particular, we focus on the current knowledge on its structure, its physico-chemical properties and its subcellular localization. Data on the involvement of GBA2 in physiopathological processes are also described, with particular emphasis on the studies that have indicated the direct involvement of GBA2 in neuronal development and neurological disorders. A discussion of some open questions and future perspectives related to GBA2 are finally reported. We conclude that further investigations on this β-glucosylceramidase will provide new clues about the physiology of the central nervous system. [ABSTRACT FROM AUTHOR]

The plasma membrane-associated sialidase NEU3 plays crucial roles in regulation of transmembrane signaling, and its aberrant up-regulation in various cancers contributes to malignancy. However, it remains uncertain how NEU3 is naturally activated and locates to plasma membranes, because of its Triton X-100 requirement for the sialidase activity in vitro and its often changing subcellular location. Among phospholipids examined, we demonstrate that phosphatidic acid (PA) elevates its sialidase activity 4 to 5 times at 50 µM in vitro at neutral pHand promotes translocation to the cell surface and cell migration through Ras-signaling in HeLa and COS-1 cells. NEU3 was found to interact selectively with PA as assessed by phospholipid array, liposome coprecipitation, and ELISA assays and to colocalize with phospholipaseD(PLD) 1 in response to epidermal growth factor (EGF) or serum stimulation. Studies using tagged NEU3 fragments with point mutations identified PA- and calmodulin (CaM)-binding sites around the N terminus and confirmed its participation in translocation and catalytic activity. EGF induced PLD1 activation concomitantly with enhancedNEU3 translocation to the cell surface, as assessed by confocal microscopy. These results suggest that interactions of NEU3 with PA produced by PLD1 are important for regulation of transmembrane signaling, this aberrant acceleration probably promoting malignancy in cancers. [ABSTRACT FROM AUTHOR]