Functional characterization of enzymes catalyzing ceramide phosphoethanolamine biosynthesis in mice

Autor(en): Bickert, Andreas
Ginkel, Christina
Kol, Matthijs
vom Dorp, Katharina
Jastrow, Holger
Degen, Joachim
Jacobs, Rene L.
Vance, Dennis E.
Winterhager, Elke
Jiang, Xian-Cheng
Doermann, Peter
Somerharju, Pentti
Holthuis, Joost C. M.
Willecke, Klaus
Stichwörter: APOPTOSIS; Biochemistry & Molecular Biology; brain lipids; CELLS; enzyme inactivation; EXPRESSION; genetics; HOMEOSTASIS; mass spectrometry; MEMBRANE SPHINGOMYELIN; PLASMA; PROTEIN SMSR; RAT-LIVER; SMS2 DEFICIENCY; sphingolipids; sphingomyelin synthase; SPHINGOMYELIN SYNTHASE 2; sphingomyelin synthase-related protein; sterile alpha motif domain-containing protein 8; transgenic mice
Erscheinungsdatum: 2015
Herausgeber: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Enthalten in: JOURNAL OF LIPID RESEARCH
Band: 56
Ausgabe: 4
Startseite: 821
Seitenende: 835
Zusammenfassung: 
Besides bulk amounts of SM, mammalian cells produce small quantities of the SM analog ceramide phosphoethanolamine (CPE). Little is known about the biological role of CPE or enzymes responsible for CPE production. Heterologous expression studies revealed that SM synthase (SMS) 2 is a bifunctional enzyme producing both SM and CPE, whereas SMS-related protein (SMSr) serves as monofunctional CPE synthase. Acute disruption of SMSr catalytic activity in cultured cells causes a rise in endoplasmic reticulum (ER) ceramides, fragmentation of ER exit sites, and induction of mitochondrial apoptosis. To address the relevance of CPE biosynthesis in vivo, we analyzed the tissue-specific distribution of CPE in mice and generated mouse lines lacking SMSr and SMS2 catalytic activity. We found that CPE levels were >300-fold lower than SM in all tissues examined. Unexpectedly, combined inactivation of SMSr and SMS2 significantly reduced, but did not eliminate, tissue-specific CPE pools and had no obvious impact on mouse development or fertility. While SMSr is widely expressed and serves as the principal CPE synthase in the brain, blocking its catalytic activity did not affect ceramide levels or secretory pathway integrity in the brain or any other tissue. Our data provide a first inventory of CPE species and CPE-biosynthetic enzymes in mammals.
ISSN: 00222275
DOI: 10.1194/jlr.M055269

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