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; Kritharides, Leonard

doi:10.1074/jbc.m114.612341

Cited by 37 publications

(43 citation statements)

References 63 publications

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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%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…High resolution cutoff was guided by the correlation coefficient CC 3355 (176) 3932 (377) 1957 (114) 1983 (112) 4411 ( SMPDL3A is part of a superfamily of phosphoesterases that utilize two metal cations for catalysis. Although ASMase is known to require zinc for activity (5), SMPDL3A was shown to be inhibited by zinc (11). As all metal-coordinating residues are conserved between both proteins (Fig.…”

Section: X-ray Data Collection and Structure Refinement Statisticsmentioning

confidence: 99%

“…Surprisingly, the enzyme was found to be inactive against SM or other lipids but instead active in the hydrolysis of nucleotide diphosphates and triphosphates (11). An anti-inflammatory role as a moderator of nucleotide-based purinergic signaling was, therefore, proposed for this protein.…”

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confidence: 99%

“…More recently, SMPDL3A was reported to be a phosphoesterase up-regulated by cholesterol in macrophages (11). Surprisingly, the enzyme was found to be inactive against SM or other lipids but instead active in the hydrolysis of nucleotide diphosphates and triphosphates (11).…”

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confidence: 99%

“…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).…”

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confidence: 99%

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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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Deregulation of obesity-relevant genes is associated with progression in BMI and the amount of adipose tissue in pigs

et al. 2017

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The aim of this study was to elucidate the relative impact of three phenotypes often used to characterize obesity on perturbation of molecular pathways involved in obesity. The three obesity-related phenotypes are (1) body mass index (BMI), (2) amount of subcutaneous adipose tissue (SATa), and (3) amount of retroperitoneal adipose tissue (RPATa). Although it is generally accepted that increasing amount of RPATa is 'unhealthy', a direct comparison of the relative impact of the three obesity-related phenotypes on gene expression has, to our knowledge, not been performed previously. We have used multiple linear models to analyze altered gene expression of selected obesity-related genes in tissues collected from 19 female pigs phenotypically characterized with respect to the obesity-related phenotypes. Gene expression was assessed by high-throughput qPCR in RNA from liver, skeletal muscle and abdominal adipose tissue. The stringent statistical approach used in the study has increased the power of the analysis compared to the classical approach of analysis in divergent groups of individuals. Our approach led to the identification of key components of cellular pathways that are modulated in the three tissues in association with changes in the three obesity-relevant phenotypes (BMI, SATa and RPATa). The deregulated pathways are involved in biosynthesis and transcript regulation in adipocytes, in lipid transport, lipolysis and metabolism, and in inflammatory responses. Deregulation seemed more comprehensive in liver (23 genes) compared to abdominal adipose tissue (10 genes) and muscle (3 genes). Notably, the study supports the notion that excess amount of intra-abdominal adipose tissue is associated with a greater metabolic disease risk. Our results provide molecular support for this notion by demonstrating that increasing amount of RPATa has a higher impact on perturbation of cellular pathways influencing obesity and obesity-related metabolic traits compared to increase in BMI and amount of SATa.

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

Cited by 37 publications

References 63 publications

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

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

Deregulation of obesity-relevant genes is associated with progression in BMI and the amount of adipose tissue in pigs

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