Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (<i>SMPDL3A</i>) by Liver X Receptors

Noto, Paul; Bukhtiyarov, Yuri; Shi, Meng; McKeever, Brian; McGeehan, Gerard M.; Lala, Deepak S.

doi:10.1124/mol.112.078865

Cited by 22 publications

(22 citation statements)

References 29 publications

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“…SMPDL3A mRNA was also up-regulated by treatment with a second LXR ligand, 22-hydroxycholesterol (data not shown). These results are consistent with other studies published while this work was underway, which demonstrated that SMPDL3A mRNA expression is increased by LXR ligands in the immortalized human leukemic THP-1 macrophage cell line and in undifferentiated human peripheral blood mononuclear cells (8,9).…”

Section: Smpdl3a Expression and Secretion Is Up-regulated By Cholestesupporting

confidence: 83%

“…SMPDL3A was originally identified as a gene up-regulated in bladder tumor versus healthy urothelium tissue (7), and more recently it has been shown to be regulated by liver X receptor (LXR) ligands in human macrophage cell lines (8,9). Beyond these observations, little is known about the biochemistry or function of SMPDL3A.…”

Section: Increased Expression and Secretion Of Smpdl3a By Cholesterolmentioning

confidence: 99%

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Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

Traini

Quinn

Sandoval

et al. 2014

Journal of Biological Chemistry

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Background: Cholesterol-loaded macrophages are key mediators of atherosclerosis and demonstrate increased SMPDL3A expression and secretion. Results: SMPDL3A expression is stimulated by cholesterol, liver X receptor ligands, and cAMP and hydrolyzes nucleotide phosphates. Conclusion: SMPDL3A is a nucleotide phosphodiesterase secreted from cholesterol-loaded macrophages. Significance: SMPDL3A possesses a novel enzymatic activity with potential relevance to atherosclerosis.

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Section: Smpdl3a Expression and Secretion Is Up-regulated By Cholestesupporting

confidence: 83%

Section: Increased Expression and Secretion Of Smpdl3a By Cholesterolmentioning

confidence: 99%

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

Traini

Quinn

Sandoval

et al. 2014

Journal of Biological Chemistry

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“…95 51,99). New targets revealed in this study include SMPDL3A, which could be another important ccRCC-specific oncogene given its role in lipid and cholesterol metabolism (61,100). Genes associated with lost superenhancers, which could only be identified with normal-tumor pairs, implicated potential tumor suppressors (EHF, MAL, GCOM1, and HOXB9) that warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…SMPDL3A shares 31% amino acid identity with the acid sphingomyelinase SMPD1 and is a target of a master regulator of cholesterol metabolism, liver X receptors (LXR; ref. 61).…”

Section: Researchmentioning

confidence: 99%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

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Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

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“…The substrate and function of SMPDL3A, however, are less clear. This enzyme is secreted by osteoclasts (8), adipocytes (9), astrocytes (10), and macrophages (11), where it is up-regulated by the activation of the liver X receptor (12,13). In the serum, SMPDL3A interacts with apolipoprotein A1 (14,15).…”

mentioning

confidence: 99%

Structural Basis for Nucleotide Hydrolysis by the Acid Sphingomyelinase-like Phosphodiesterase SMPDL3A

Gorelik

Illés

Superti‐Furga

et al. 2016

Journal of Biological Chemistry

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Sphingomyelin phosphodiesterase, acid-like 3A (SMPDL3A) is a member of a small family of proteins founded by the well characterized lysosomal enzyme, acid sphingomyelinase (ASMase). ASMase converts sphingomyelin into the signaling lipid, ceramide. It was recently discovered that, in contrast to ASMase, SMPDL3A is inactive against sphingomyelin and, surprisingly, can instead hydrolyze nucleoside diphosphates and triphosphates, which may play a role in purinergic signaling. As none of the ASMase-like proteins has been structurally characterized to date, the molecular basis for their substrate preferences is unknown. Here we report crystal structures of murine SMPDL3A, which represent the first structures of an ASMaselike protein. The catalytic domain consists of a central mixed ␤-sandwich surrounded by ␣-helices. Additionally, SMPDL3A possesses a unique C-terminal domain formed from a cluster of four ␣-helices that appears to distinguish this protein family from other phosphoesterases. We show that SMDPL3A is a di-zinc-dependent enzyme with an active site configuration that suggests a mechanism of phosphodiester hydrolysis by a metal-activated water molecule and protonation of the leaving group by a histidine residue. Co-crystal structures of SMPDL3A with AMP and ␣,␤-methylene ADP (AMPCP) reveal that the substrate binding site accommodates nucleotides by establishing interactions with their base, sugar, and phosphate moieties, with the latter the major contributor to binding affinity. Our study provides the structural basis for SMPDL3A substrate specificity and sheds new light on the function of ASMase-like proteins.

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Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A) by Liver X Receptors

Cited by 22 publications

References 29 publications

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Structural Basis for Nucleotide Hydrolysis by the Acid Sphingomyelinase-like Phosphodiesterase SMPDL3A

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