CERAMIDE SYNTHASE 1 IS REGULATED BY PROTEASOMAL MEDIATED TURNOVER
By P. Sridevi, Hannah Alexander, Elad L. Laviad, Y. Pewzner‐Jung, Mark Hannink, A. Futerman, S. Alexander. 2009
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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.
Subfields: Biochemistry, Molecular Biology
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Citations in the corpus
- Mammalian Ceramide Synthases (2010, background): “CerS1 is also phosphorylated in vivo, and activation of protein kinase C (PKC) increases its phosphorylation (45), with turnover regulated by the opposing functions of p38 MAP kinase and PKC, such that p38 MAP kinase acts as a positive regulator of turnover while PKC is a negative regulator.”
- Stress-induced ER to Golgi translocation of ceramide synthase 1 is dependent on proteasomal processing (2009, unknown): “It should be noted that BIM inhibits five of eight PKC isoforms and further experiments will be necessary to identify which specific isoform(s) is regulating CerS1.”