Inactivation of ceramide synthase 2 catalytic activity in mice affects transcription of genes involved in lipid metabolism and cell division

Bickert, Andreas; Kern, Paul; Uelft, Martina van; Herresthal, Stefanie; Ulas, Thomas; Gutbrod, Katharina; Breiden, Bernadette; Degen, Joachim; Sandhoff, Konrad; Schultze, Joachim L.; Dörmann, Peter; Hartmann, Dieter; Bauer, Reinhard; Willecke, Klaus

doi:10.1016/j.bbalip.2018.04.006

Cited by 17 publications

(12 citation statements)

References 63 publications

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“…Significant progress has been made in understanding the modes of regulation of the CerSs since their initial discovery in mammalian cells ∼20 years ago ( 24 ), largely based on bioinformatics analyses as well as site-directed mutagenesis and domain-swapping experiments ( 5 , 10 , 11 , 16 , 25 ). Various motifs and domains have been identified, with most attention paid to the Lag1p motif ( 13 , 24 , 26 ), likely containing the active site, and to the TLC domain in which the Lag1p motif resides.…”

Section: Discussionmentioning

confidence: 99%

A novel C-terminal DxRSDxE motif in ceramide synthases involved in dimer formation

Kim

Ben‐Dor

Rosenfeld-Gur

et al. 2022

Journal of Biological Chemistry

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Ceramide is a lipid moiety synthesized via the enzymatic activity of ceramide synthases (CerSs), six of which have been identified in mammalian cells, and each of which uses a unique subset of acyl-CoAs for ceramide synthesis. The CerSs are part of a larger gene family, the T ram- L ag- C LN8 domain family. Here, we identify a unique, C-terminal motif, the DxRSDxE motif, which is only found in CerSs and not in other T ram- L ag- C LN8 family members. Deletion of this motif in either CerS2 or in CerS6 did not affect the ability of either enzyme to generate ceramide using both an in vitro assay and metabolic labeling, but deletion of this motif did affect the activity of CerS2 when coexpressed with CerS6. Surprisingly, transfection of cells with either CerS2 or CerS6 lacking the motif did not result in changes in cellular ceramide levels. We found that CerS2 and CerS6 interact with each other, as shown by immunoprecipitation, but deletion of the DxRSDxE motif impeded this interaction. Moreover, proteomics analysis of cells transfected with CerS6 Δ338–344 indicated that deletion of the C-terminal motif impacted cellular protein expression, and in particular, the levels of ORMDL1, a negative regulator of sphingolipid synthesis. We suggest that this novel C-terminal motif regulates CerS dimer formation and thereby impacts ceramide synthesis.

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Section: Discussionmentioning

confidence: 99%

A novel C-terminal DxRSDxE motif in ceramide synthases involved in dimer formation

Kim

Ben‐Dor

Rosenfeld-Gur

et al. 2022

Journal of Biological Chemistry

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“…The C-terminus of CerS2 may regulate the interaction with FATP2 -To attempt to determine which structural domains of CerS2 are involved in the binding to FATP2, we took advantage of a series of CerS2 mutations and deletion constructs (10,27,28). Deletion of the Hox-like domain (27) had no effect on the extent of immunoprecipitation of CerS2 with FATP2 in CerS2 -/-HEK cells, and neither did replacement of the two putative active site residues (HH 212-213 AA) (28) (Fig.…”

Section: Fatps Interact With Cers2 and Modulate Cellular Sl Levels -mentioning

confidence: 99%

“…Effect of CerS2 mutations on binding to FATP2. A, Schematic representation of the domains of CerS2-HA with the site of the mutations (10,27,28) color coded as in B. The numbers indicate the position of amino acid residues in the sequence.…”

Section: Figure Legendsmentioning

confidence: 99%

Fatty acid transport protein 2 interacts with ceramide synthase 2 to promote ceramide synthesis

Kim

Mestre

Malitsky

et al. 2022

Journal of Biological Chemistry

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“…CerS2 generates longer C22-C24 ceramides and was similarly found to be downregulated in many cancers. Mice that expressed a catalytically inactive mutant CerS2 developed hepatocellular carcinoma (HCC) at a young age (8 weeks), while mice that were deficient for CerS2 developed liver adenoma and HCC later in adulthood (7-10 months) [76][77][78]. Similarly, CerS2 knockout mice were susceptible to azoxymethane induction of colon carcinoma and dextran sodium sulfate induction of colitis [36].…”

Section: Ceramide Synthases 1-6mentioning

confidence: 99%

The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy

Sheridan

Öğretmen

2021

Cancers

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Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid’s specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy.

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Inactivation of ceramide synthase 2 catalytic activity in mice affects transcription of genes involved in lipid metabolism and cell division

Cited by 17 publications

References 63 publications

A novel C-terminal DxRSDxE motif in ceramide synthases involved in dimer formation

A novel C-terminal DxRSDxE motif in ceramide synthases involved in dimer formation

Fatty acid transport protein 2 interacts with ceramide synthase 2 to promote ceramide synthesis

The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy

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