title: Regulation of CC ligand 5/RANTES by acid sphingomyelinase and acid ceramidase.
abstract: Acid sphingomyelinase (aSMase) generates the bioactive lipid ceramide (Cer) from hydrolysis of sphingomyelin (SM). However, its precise roles in regulating specific sphingolipid-mediated biological processes remain ill defined. Interestingly, the aSMase gene gives rise to two distinct enzymes, lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase) via alternative trafficking of a shared protein precursor. Previously, our laboratory identified Ser(508) as a crucial residue for the constitutive and regulated secretion of S-SMase in response to inflammatory cytokines, and demonstrated a role for S-SMase in formation of select cellular Cer species (Jenkins, R. W., Canals, D., Idkowiak-Baldys, J., Simbari, F., Roddy, P., Perry, D. M., Kitatani, K., Luberto, C., and Hannun, Y. A. (2010) J. Biol. Chem. 285, 35706-35718). In the present study using a chemokine/cytokine screen, we identified the chemokine CCL5 (formerly known as RANTES) as a candidate-specific downstream target for aSMase. Regulation of CCL5 by aSMase was subsequently validated using both loss-of-function and gain-of-function models indicating that aSMase is both necessary and sufficient for CCL5 production. Interestingly, cells deficient in acid ceramidase (aCDase) also exhibited defects in CCL5 induction, whereas cells deficient in sphingosine kinase-1 and -2 exhibited higher levels of CCL5, suggesting that sphingosine and not sphingosine 1-phosphate (S1P) is responsible for the positive signal to CCL5. Consistent with this, co-expression of aSMase and aCDase was sufficient to strongly induce CCL5. Taken together, these data identify a novel role for aSMase (particularly S-SMase) in chemokine elaboration by pro-inflammatory cytokines and highlight a novel and shared function for aSMase and aCDase.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Jenkins
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Clarke
authors.forename: Daniel
authors.initials: D
authors.lastname: Canals
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Snider
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gault
authors.forename: Linda
authors.initials: L
authors.lastname: Heffernan-Stroud
authors.forename: Bill X
authors.initials: BX
authors.lastname: Wu
authors.forename: Fabio
authors.initials: F
authors.lastname: Simbari
authors.forename: Patrick
authors.initials: P
authors.lastname: Roddy
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kitatani
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D055577:Farber Lipogranulomatosis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism*
chemical_list: C483024:CCL5 protein, human; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; C112980:acid sphingomyelinase-1; C112981:acid sphingomyelinase-2; D013108:Sphingomyelin Phosphodiesterase; D055573:Acid Ceramidase; D013110:Sphingosine