Ceramide synthase 1 explained

Ceramide synthase 1 also known as LAG1 longevity assurance homolog 1 is an enzyme that in humans is encoded by the CERS1 gene.^{[1] [2] [3]}

Function

This gene encodes a member of the bone morphogenetic protein (BMP) family and the TGF-beta superfamily. This group of proteins is characterized by a polybasic proteolytic processing site that is cleaved to produce a mature protein containing seven conserved cysteine residues. Members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies in yeast suggest that the encoded protein is involved in aging. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1.

Ceramide synthase 1 (CerS1) is a ceramide synthase that catalyzes the synthesis of C18 ceramide in a fumonisin B1-independent manner, and is primarily expressed in the brain.^[4] It can also be found in low levels in skeletal muscle and the testis.^[5] Within the cell, CerS1 is located in the endoplasmic reticulum (ER) and golgi apparatus membrane. CerS1 has two isoforms and isoform 1 may recycle from the golgi to the ER.^[6]

CerS1/GDF1 mRNA is strongly expressed in muscle and brain, and was also found in heart and lung.^[7] Within the brain, CerS1 is the primary CerS expressed in most neurons. In white matter, it can only be found in low levels.^[8]

In an experiment performed in mice in 2012, ablation of neuronal CerS1 decreased levels of sphingolipids, hexosylceramides, and sphingomyelin. Although the brains in these mice appeared to develop normally, researchers observed atrophy of the cerebellum, and Purkinje neurons appeared to degenerate. Granule cells also showed a 6 times increased rate of apoptosis. Behaviorally, the mice expressed motor and neurophysiological impairment.

Structure

Unlike other mammalian ceramides, CerS1 does not appear to have a Hox-like domain. It is functionally and structurally distinct from other CerS and is found in an entirely different branch of the phylogenetic tree.

Clinical significance

On application of various stresses, CerS1 turns over rapidly by ubiquitination and proteasomal degradation, suggesting that it has a short half life.

It has been suggested that CerS1 is involved with the regulation of the growth of head and neck squamous cell carcinoma (HNSCC), based on the information that C18 ceramide levels are lower in HNSCC tissues than in normal tissue. CerS1, in particular amongst other CerS, has also been shown to sensitize cells to chemotherapeutic drugs, such as cisplatin, carboplatin, doxorubicin, and vincristine.

Further reading

• Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Koybasi S, Senkal CE, Sundararaj K . Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas . J. Biol. Chem. . 279 . 43 . 44311–9 . 2004 . 15317812 . 10.1074/jbc.M406920200 . etal. free .
• Grimwood J, Gordon LA, Olsen A . The DNA sequence and biology of human chromosome 19 . Nature . 428 . 6982 . 529–35 . 2004 . 15057824 . 10.1038/nature02399 . 2004Natur.428..529G . etal. free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• Venkataraman K, Riebeling C, Bodennec J . Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells . J. Biol. Chem. . 277 . 38 . 35642–9 . 2002 . 12105227 . 10.1074/jbc.M205211200 . etal. free .

Notes and References

1. Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM . Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human . Genome Res . 8 . 12 . 1259–72 . Jun 1999 . 9872981 . 10.1101/gr.8.12.1259. free .
2. Lee SJ . Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure . Proc Natl Acad Sci U S A . 88 . 10 . 4250–4 . Jun 1991 . 2034669 . 51636 . 10.1073/pnas.88.10.4250 . free . 1991PNAS...88.4250L .
3. Web site: Entrez Gene: LASS1 LAG1 homolog, ceramide synthase 1 (S. cerevisiae).
4. Ginkel C, Hartmann D, vom Dorp K, Zlomuzica A, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Rabionet M, Dere E, Dörmann P, Sandhoff K, Willecke K . Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes . J. Biol. Chem. . 287 . 50 . 41888–902 . December 2012 . 23074226 . 3516736 . 10.1074/jbc.M112.413500 . free .
5. Levy M, Futerman AH . Mammalian ceramide synthases . IUBMB Life . 62 . 5 . 347–56 . May 2010 . 20222015 . 2858252 . 10.1002/iub.319 .
6. Web site: Ceramide synthase 1. EBI.ac.uk . EMBL-EBI . 2014 . 16 February 2014.
7. Riebeling C, Allegood JC, Wang E, ((Merrill AH Jr)), Futerman AH . Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors . J Biol Chem . 278. 44 . 43452–9 . Oct 2003 . 12912983 . 10.1074/jbc.M307104200 . free .
8. Becker I, Wang-Eckhardt L, Yaghootfam A, Gieselmann V, Eckhardt M . Differential expression of (dihydro)ceramide synthases in mouse brain: oligodendrocyte-specific expression of CerS2/Lass2 . . 129 . 2 . 233–41 . February 2008 . 17901973 . 10.1007/s00418-007-0344-0 . 2595275 .