Ceramide synthase 1 is regulated by proteasomal mediated turnover.
Ceramide is an important bioactive lipid, intimately involved in many cellular functions, including the regulation of cell death, and in cancer and chemotherapy. Ceramide is synthesized de novo from sphinganine and acyl CoA via a family of 6 ceramide synthase enzymes, each having a unique preference for different fatty acyl CoA substrates and a unique tissue distribution. However, little is known regarding the regulation of these important enzymes. In this study we focus on ceramide synthase 1 (CerS1) which is the most structurally and functionally distinct of the enzymes, and describe a regulatory mechanism that specifically controls the level of CerS1 via ubiquitination and proteasome dependent protein turnover. We show that both endogenous and ectopically expressed CerS1 have rapid basal turnover and that diverse stresses including chemotherapeutic drugs, UV light and DTT can induce CerS1 turnover. The turnover requires CerS1 activity and is regulated by the opposing actions of p38 MAP kinase and protein kinase C (PKC). p38 MAP kinase is a positive regulator of turnover, while PKC is a negative regulator of turnover. CerS1 is phosphorylated in vivo and activation of PKC increases the phosphorylation of the protein. This study reveals a novel and highly specific mechanism by which CerS1 protein levels are regulated and which directly impacts ceramide homeostasis.
Sridevi
Priya
P
Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA.
Alexander
Hannah
H
Laviad
Elad L
EL
Pewzner-Jung
Yael
Y
Hannink
Mark
M
Futerman
Anthony H
AH
Alexander
Stephen
S
D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D025801:Ubiquitin; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex