Sphingomyelin phosphodiesterase Acid-like 3A (SMPDL3A) is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages

Traini, Mathew, Quinn, Carmel M., Sandoval, Cecilia, Johansson, Erik, Schroder, Kate, Kockx, Maaike, Meikle, Peter J., Jessup, Wendy and Kritharides, Leonard (2014) Sphingomyelin phosphodiesterase Acid-like 3A (SMPDL3A) is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages. Journal of Biological Chemistry, 289 47: 32895-32913. doi:10.1074/jbc.M114.612341

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Author Traini, Mathew
Quinn, Carmel M.
Sandoval, Cecilia
Johansson, Erik
Schroder, Kate
Kockx, Maaike
Meikle, Peter J.
Jessup, Wendy
Kritharides, Leonard
Title Sphingomyelin phosphodiesterase Acid-like 3A (SMPDL3A) is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2014-10-06
Sub-type Article (original research)
DOI 10.1074/jbc.M114.612341
Open Access Status File (Publisher version)
Volume 289
Issue 47
Start page 32895
End page 32913
Total pages 19
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
Cholesterol-loaded foam cell macrophages are prominent in atherosclerotic lesions and play complex roles in both inflammatory signaling and lipid metabolism, which are underpinned by large scale reprogramming of gene expression. We performed a microarray study of primary human macrophages that showed that transcription of the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene is up-regulated after cholesterol loading. SMPDL3A protein expression in and secretion from primary macrophages are stimulated by cholesterol loading, liver X receptor ligands, and cyclic AMP, and N-glycosylated SMPDL3A protein is detectable in circulating blood. We demonstrate for the first time that SMPDL3A is a functional phosphodiesterase with an acidic pH optimum. We provide evidence that SMPDL3A is not an acid sphingomyelinase but unexpectedly is active against nucleotide diphosphate and triphosphate substrates at acidic and neutral pH. SMPDL3A is a major source of nucleotide phosphodiesterase activity secreted by liver X receptor-stimulated human macrophages. Extracellular nucleotides such as ATP may activate pro-inflammatory responses in immune cells. Increased expression and secretion of SMPDL3A by cholesterol-loaded macrophage foam cells in lesions may decrease local concentrations of pro-inflammatory nucleotides and potentially represent a novel anti-inflammatory axis linking lipid metabolism with purinergic signaling in atherosclerosis.
Keyword Atherosclerosis
Cholesterol
Macrophage
Metalloenzyme
Phosphodiesterases
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 28 Nov 2014, 00:53:01 EST by Katrina Garner-Moore on behalf of Institute for Molecular Bioscience