Intermediates of phospholipid (PL) and sphingolipid (SL) metabolism serve as second messengers for a number of signaling cascades including activation of G-protein-coupled receptors such as adrenaline, thrombin, etc., as well as receptor tyrosine kinases by growth factors. They mediate a number of processes ranging from protein secretion to activation of apoptosis. We have initiated studies to understand different aspects of lipid signaling in Drosophila.Lipid Reservoirs and Signaling. Sphingomyelin (or phosphorylethanolamine ceramide in flies) could serve as a reservoir for several lipid messengers such as ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. We have initiated studies to delineate the in vivo role of some of the enzymes of the putative 'Sphingomyelin Cycle'. We have begun by identifying homologous genes in Drosophila. We are using transgenic and mutagenic studies to analyse the importance of such a pathway in Drosophila. We have recently demonstrated that modulation of the sphingolipid biosynthetic pathway such as targeted expression of ceramidase, rescues degeneration in certain photoreceptor mutants. We have also demonstrated that ceramidase facilitates membrane turnover and rhodopsin endocytosis in Drosophila photoreceptors.Lipid Distribution and Signaling.PL and SL at the plasma membrane play an important role in stimulus-response coupling, cell differentiation, movement, and exo- and endocytosis. They are asymmetrically distributed in biological membranes, and different proteins catalyzing uni- and bi-directional movements of lipids perpetuate asymmetry. Our current efforts focus on scramblase, a protein proposed to be involved in bi-directional transbilayer movement of phospholipids. We have recently completed two genetic screens and obtained Drosophila flies lacking two of the identified scramblase proteins. We have also generated flies lacking both genes (double mutants). Phenotypic analysis of double mutant indicate that surprisingly scramblases do not have a determining role in scrambling of phospholipids that accompany apoptosis, phagocytosis and fusion. Instead, they play a regulatory role in regulated exocytosis. This has implication in a wide range of cellular processes involving digestive system and endocrine and exocrine secretions with clinical relevance in a wide range of diseases such as diabetes, behavior and even tumor metastasis.We anticipate that a combination of genetic, molecular, and biochemical approaches in Drosophila will define the important players involved in PL, SL signaling in their normal cellular environment.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Basic Sciences
United States
Zip Code
Rao, Raghavendra Pralhada; Acharya, Jairaj K (2008) Sphingolipids and membrane biology as determined from genetic models. Prostaglandins Other Lipid Mediat 85:1-16
Rao, Raghavendra Pralhada; Yuan, Changqing; Allegood, Jeremy C et al. (2007) Ceramide transfer protein function is essential for normal oxidative stress response and lifespan. Proc Natl Acad Sci U S A 104:11364-9
Acharya, Usha; Edwards, Michael Beth; Jorquera, Ramon A et al. (2006) Drosophila melanogaster Scramblases modulate synaptic transmission. J Cell Biol 173:69-82
Acharya, U; Acharya, J K (2005) Enzymes of sphingolipid metabolism in Drosophila melanogaster. Cell Mol Life Sci 62:128-42
Acharya, Usha; Mowen, Michael Beth; Nagashima, Kunio et al. (2004) Ceramidase expression facilitates membrane turnover and endocytosis of rhodopsin in photoreceptors. Proc Natl Acad Sci U S A 101:1922-6
Rohrbough, Jeffrey; Rushton, Emma; Palanker, Laura et al. (2004) Ceramidase regulates synaptic vesicle exocytosis and trafficking. J Neurosci 24:7789-803
Acharya, Usha; Patel, Shetal; Koundakjian, Edmund et al. (2003) Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration. Science 299:1740-3