Jairaj K. Acharya, MBBS, Ph.D.
We are interested in understanding the complex interrelationship between phospholipid (PL) and sphinolipid (SL) metabolism and metabolic signaling in vivo. Our studies are investigating several aspects of lipid signaling in Drosophila.
1) phospholipid (PL) metabolism, 2) sphingolipid (SL) metabolism, 3) metabolic signaling
Our long-term objective is to understand the complex interrelationship between phospholipid and sphingolipid metabolism and metabolic signaling in vivo. 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 and thrombin 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 several aspects of lipid signaling in Drosophila.
Lipid Reservoirs and Signaling
Sphingomyelin (or phosphorylethanolamine ceramide, CPE, 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 gain of function and mutagenic loss of function studies to analyze 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.
Sphingolipids are synthesized vectorially. While the steps that lead up to the generation of ceramide occurs in the endoplasmic reticulum (ER) the biosynthesis of sphingomyelin(or CPE) and most complex sphingolipids occurs outside of the ER, either in the Golgi Complex or in the plasma membrane. This necessitates the active transport of ceramide from ER to the Golgi Complex. The transport is largely mediated by a protein called ceramide transfer protein (CERT). We have now demonstrated that CERT-mediated transfer of ceramide is critical for the biosynthesis of sphingomyelin (or CPE in Drosophila) and complex sphingolipids. Lack of CERT in Drosophila leads to decreased CPE and they have plasma membranes with altered physical and physiological properties. The changes render them susceptible to normal loads of reactive oxygen species encountered in a cell. The ensuing oxidative damage of plasma membrane leads to production of lipid peroxides that will further oxidize membrane and cellular constituents leading to a rapid deterioration in the metabolic function of cell. The underlying pathoglogic changes manifest as accelerated aging in these mutant flies and consequently they have a short adult life span.
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 bidirectional movements of lipids perpetuate asymmetry. Our initial studies involving the generation and characterization of mutants of scramblases in Drosophila indicate a modulatory role for these proteins in regulated exocytosis and no determining role in scrambling of phospholipids. This has implications in a wide range of cellular processes. Further studies should enable us to dissect its role further.
Selected Recent Publications
- Proc Natl Acad Sci U S A. 2018. [ Journal Article ]
- Cell Death Dis. 5: e1240, 2014. [ Journal Article ]
Ceramide transfer protein deficiency compromises organelle function and leads to senescence in primary cells.PLoS ONE. 9: e92142, 2014. [ Journal Article ]
- J. Cell Biol. 2014. [ Journal Article ]
Phosphatidic acid phospholipase A1 mediates ER-Golgi transit of a family of G protein-coupled receptors.J. Cell Biol. 206: 79-95, 2014. [ Journal Article ]
Dr. Jairaj Acharya obtained his M.B.B.S. from the University of Gulbarga (Government Medical College, Bellary), India, in 1985 and received his Ph.D. in biochemistry from the Indian Institute of Science, Bangalore, in 1993 under Prof. Appaji Rao. He joined Dr. Charles Zuker at the University of California, San Diego as an associate of the Howard Hughes Medical Institute for his postdoctoral training. He was recruited by the NCI in 1999.
|Parthibane Velayoudame Ph.D.||Biologist (Contr.)|
|Govind Kunduri Ph.D.||Research Fellow (Visiting)|
|Thiruvaimozhi Abimannan Ph.D.||Postdoctoral Fellow (Visiting)|
|Kenneth Kim||Postbaccalaureate Fellow (CRTA)|
Associate Medical Affairs Manager
University of Massachusetts Medical School
Laboratory of Protein Dynamics and Signaling
Center for Cancer Research, NCI
University of Maryland, College Park
Drug Target Validation Group
Connexios Life Sciences
Center for Genetic Medicine Research
Children's National Medical Center
Laboratory of Experimental Carcinogenesis
Center for Cancer Research, NCI
The Acharya Lab Team
The Lab - Summer 2013
Sitting - left to right: Hirsh, Prateek and Jairaj
Standing - left to right: Govind, Katie, Zach, Jing Lin, Rishabh, Desh,
Parthi, Jing jing, Abhishek, Suzanne and Teresa
Honorary Lab Member: Suzanne Specht
The Lab - August 2012
Sitting - left to right: Jairaj, Yasmin, Jing-jing, Jing Lin
Standing - left to right: Razi, Teresa, Anish, Zach, Desh, Rishabh,
Rohan and Surabhi Missing: Meena
The Lab - 2011
Left to Right: Teresa, Odilia, Zach, Diwash, Srideshikan, Meena,
Jing Lin, Jing-jing, Priyanka, Jairaj and Razi Missing: Shelby
Summer 2010 with the Interns*
Sitting - left to right: Razi, Daniel* and Jairaj
Standing - left to right: Malini*, Teresa, Luana, Pauline*, Rags,
Jing-jing, Advait*, Abid, Tanvi* and Diwash
The Lab - April 2010
Interns with Diwash - 2010
Left to Right: Malini, Tanvi, Pauline, Diwash, Advait, and Daniel
With the Summer Interns on Their Last Day - August 2009
Left to Right: Daniel, Razi, Raghavendra, Diwash, Teresa, Alexandra, Stephanie, Joyce, Abid and Jairaj
Yana and Changqing's Baby Shower - May 2009
The Lab - February 2009
Daniel, Josh, and Changqing: Student, Soldier/Teacher, and Postdoc - 2009
The Lab - August 2008