title: Ceramide transfer protein function is essential for normal oxidative stress response and lifespan.
abstract: Ceramide transfer protein (CERT) transfers ceramide from the endoplasmic reticulum to the Golgi complex, a process critical in synthesis and maintenance of normal levels of sphingolipids in mammalian cells. However, how its function is integrated into development and physiology of the animal is less clear. Here, we report the in vivo consequences of loss of functional CERT protein. We generated Drosophila melanogaster mutant flies lacking a functional CERT (Dcert) protein using chemical mutagenesis and a Western blot-based genetic screen. The mutant flies die early between days 10 and 30, whereas controls lived between 75 and 90 days. They display >70% decrease in ceramide phosphoethanolamine (the sphingomyelin analog in Drosophila) and ceramide. These changes resulted in increased plasma membrane fluidity that renders them susceptible to reactive oxygen species and results in enhanced oxidative damage to cellular proteins. Consequently, the flies showed reduced thermal tolerance that was exacerbated with aging and metabolic compromise such as decreasing ATP and increasing glucose levels, reminiscent of premature aging. Our studies demonstrate that maintenance of physiological levels of ceramide phosphoethanolamine by CERT in vivo is required to prevent oxidative damages to cellular components that are critical for viability and normal lifespan of the animal.
authors.affiliation: Laboratory of Cell and Developmental Signaling, National Cancer Institute Frederick, Frederick, MD 21702, USA.
authors.forename: Raghavendra Pralhada
authors.initials: RP
authors.lastname: Rao
authors.forename: Changqing
authors.initials: C
authors.lastname: Yuan
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.forename: Satinder S
authors.initials: SS
authors.lastname: Rawat
authors.forename: Michael Beth
authors.initials: MB
authors.lastname: Edwards
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: Usha
authors.initials: U
authors.lastname: Acharya
authors.forename: Jairaj K
authors.initials: JK
authors.lastname: Acharya
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002352:Carrier Proteins / Q000502:physiology*; D002518:Ceramides / Q000378:metabolism*; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*
chemical_list: C522899:CERT protein, Drosophila; D002352:Carrier Proteins; D002518:Ceramides; D029721:Drosophila Proteins