Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible crossreactivity with acid sphingomyelinaselike phosphodiesterase 3b precursor. Smpdl3b sphingomyelin phosphodiesterase acid like 3b homo. Smpdl3b gene genecards asm3b protein asm3b antibody. Jci insight b cellderived il4 acts on podocytes to. Has in vitro nucleotide phosphodiesterase activity with nucleoside triphosphates, such as atp pubmed. This study was supported, in part, by the intramural research program of the. Sphingomyelin phosphodiesterase acid like 3a smpdl3a is one of three members of the acid sphingomyelinase asmase like enzyme family, which also comprises the founding member asmase encoded by smpd1 and sphingomyelin phosphodiesterase acid like 3b smpdl3b encoded by smpdl3b.
The enzyme acid sphingomyelinase like phosphodiesterase 3b smpdl3b was shown to act as a negative regulator of innate immune signaling, affecting cellular lipid composition and membrane fluidity. Acid sphingomyelinaselike phosphodiesterase 3b uniprot. Moreover, it has been shown that rituximab binds to the sphingomyelin phosphodiesterase acidlike 3b protein in glomerular podocytes and regulates acid sphingomyelinase activity, stabilizing the actin cytoskeleton, and preventing apoptosis of podocytes, thus providing another rationale for the use of rituximab in the management of mcd. Smpdl3a functions as a cholesterol driven nucleotide phosphodiesterase 9, whereas smpdl3b was shown to be important for normal podocyte function. The lipidmodulating enzyme sphingomyelinphosphodiesterase acidlike 3bsmpdl3b is akey determinant ofpodocyte injury andaknownoff target of the anticd20 antibody rituximab rtx. George priya doss, in advances in protein chemistry and structural biology, 2016. Smpdl3a sphingomyelin phosphodiesterase acid like 3a.
Smpdl3a acid sphingomyelinaselike phosphodiesterase 3a. We observed that expression of the gene smpdl3a sphingomyelin phosphodiesterase, acidlike 3a is strongly upregulated by cholesterol loading. To confirm the binding of smpdl3b by rituximab, we overexpressed hatagged smpdl3b in 293t cells that do not. Conversely, genes upregulated by microbiota in the gut but downregulated by microbiota in the skin, include gtp cyclohydrolase i feedback regulator gchfr, phosphodiesterase 9a pde9a, marckslike 1 marcksl1, nuclear rna export factor 7 nxf7, sphingomyelin phosphodiesterase, acidlike 3b smpdl3b, glutathione peroxidase 2 gpx2, and. Using ex vivo coculture systems, cdc2s are shown to be superior in presenting. Associated with diseasescitation referencescurators 1 lovdteam, but with curator vacancy. Active on the surface of macrophages and dendritic cells and strongly influences macrophage lipid composition and. Through in vitro experiments, they confirm that rituximab does not show binding to sphingomyelin phosphodiesterase acid like 3b smpdl3b receptor on the human embryonic kidney, 293t cells. We investigated the regulation of smpdl3a gene expression by lxrs across several human and mouse cell types. The enzyme acid sphingomyelinaselike phosphodiesterase 3b smpdl3b was shown to act as a negative regulator of innate immune signaling, affecting cellular lipid composition and membrane fluidity. Acts as a negative regulator of tolllike receptor signaling pubmed. Reduction in smpdl3bpositive podocytes was observed in biopsies showing fsgs.
Rituximab therapy for focal segmental glomerulosclerosis. Sphingomyelinase phosphodiesterase acid like 3a and 3b smpdl3a and smpdl3b are the two paralogues of acid sphingomyelinase asm. Rituximab, in addition to binding to cd20, partially prevented the downregulation of the sphingomyelin phosphodiesterase acid like 3b protein and acid sphingomyelinase in podocytes treated with the sera from patients with recurrent fsgs. Study reports that smpdl3b excess, as observed in podocytes in diabetic kidney disease, impairs insulin receptor isoform bdependent prosurvival insulin signaling by interfering with insulin receptor. Rituximab targets podocytes in recurrent focal segmental. Prospects for precision medicine in glomerulonephritis. A recent study reported that the loss of sphingomyelin phosphodiesterase acidlike 3b smpdl3b in allogeneic human kidney grafts was related to the development of posttransplant proteinuria in patients with focal segmental glomerulosclerosis fsgs 18. Nov 21, 2014 we observed that expression of the gene smpdl3a sphingomyelin phosphodiesterase, acid like 3a is strongly upregulated by cholesterol loading.
Recombinant human acid sphingomyelinaselike phosphodiesterase 3bsmpdl3b yeastcsbyp835664hu licsbep835664hu baculoviruscsbbp835664hu mammalian cellcsbmp835664hu in vivo biotinylation in licsbep835664hub. Nglycosylation of human sphingomyelin phosphodiesterase. However, since this effect was limited, we expected that other mechanisms might also be involved in the induction of. Full text optimal management of primary focal segmental. Sphingomyelin phosphodiesterase acid like 3b smpdl3b affects insulin signaling in podocytes alla v. This screen identified the sphingomyelin phosphodiesterase acid like 3a smpdl3a gene as a novel lxrregulated gene, with an lxr response element within its promoter. Sphingomyelin phosphodiesterase acidlike 3b smpdl3b affects insulin signaling in podocytes alla v. Although podocytes do not express cd20, fornoni et al reported that rtx binds to podocytes by targeting sphingomyelinphosphodiesterase acidlike 3b smpdl3b, which regulates acidsphingomyelinase asmase activity. Does not have sphingomyelin phosphodiesterase activity pubmed. Sphingomyelin phosphodiesterase acidlike 3b smpdl3b is a lipid raft enzyme that regulates plasma membrane pm fluidity. Regulation of the amount of ceramide1phosphate synthesized. Smpdl3b sphingomyelin phosphodiesterase acid like 3b.
Human acid sphingomyelinaselike phosphodiesterase 3bsmpdl3b. Smpdl3a is named for its sequence homology to the well characterized acid sphingomyelinase asmase, encoded by the smpd1 gene, with which it shares 31% amino acid identity. Although a potential substrate for smpdl3b is sphingomyelin, we identify other. Smpdl3a sphingomyelin phosphodiesterase acid like 3a, authors. Sphingomyelin phosphodiesterase acidlike 3a smpdl3a is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages mathew traini 1, carmel m.
Rituximab and therapeutic plasma exchange in recurrent focal. Rituximab not only recognizes cd20 on b lymphocytes, but might also bind sphingomyelin phosphodiesterase acidlike 3b smpdl3b protein and regulate acid sphingomyelinase asmase activity. Smpdl3b, sphingomyelin phosphodiesterase acid like 3b. This screen identified the sphingomyelin phosphodiesterase acidlike 3a smpdl3a gene as a novel lxrregulated gene, with an lxr response element within its promoter. Active on the surface of macrophages and dendritic cells and strongly influences macrophage lipid composition and membrane fluidity pubmed. Through in vitro experiments, they confirm that rituximab does not show binding to sphingomyelin phosphodiesterase acidlike 3b smpdl3b receptor on. Nglycosylation of human sphingomyelin phosphodiesterase acid.
Smpdl3b elisa kit sphingomyelin phosphodiesterase, acidlike 3b details for product smpdl3b elisa kit no. Smpdl3b modulates insulin receptor signaling in diabetic. Sphingomyelinaselike phosphodiesterase 3b mediates radiation. Gene music using protein sequence of smpdl3b sphingomyelin phosphodiesterase, acidlike 3b.
Extracellular nucleotides such as atp may activate pro. We hypothesized that rituximab prevents recurrent fsgs and preserves podocyte smpdl 3b expression. Smpdl3b elisa kit sphingomyelin phosphodiesterase, acidlike 3b. Acid sphingomyelinaselike phosphodiesterase 3b smpdl3b is a protein with. Interestingly, when podocytes were induced by sera from patients with recurrent fsgs, rituximab or overexpression of sphingomyelin phosphodiesterase acidlike 3b smpdl3b was able to prevent disruption of the actin cytoskeleton and apoptosis of podocytes. Gene references into functions our results identify the membranemodulating enzyme smpdl3b as a negative regulator of tlr signaling that functions at the interface of membrane biology and innate immunity. Sphingomyelin phosphodiesterase acidlike 3a smpdl3a is.
Podocyte pathology and nephropathy sphingolipids in. Pdf sphingomyelinphosphodiesteraseacidlike3b affects. Sphingomyelin phosphodiesterase, acidlike 3b ak052580 12 12. Rituximab not only recognizes cd20 on b lymphocytes, but might also bind sphingomyelin phosphodiesterase acid like 3b smpdl 3b protein and regulate acid sphingomyelinase asmase activity. The mechanism by which rituximab affects the fsgs course does not seem to be related to its anti cd20 activity. Rnaseq analysis of 2 closely related leukemia clones that. The enzyme acid sphingomyelinaselike phosphodiesterase 3b. Rather than acting on antibody production directly, rituximab might prevent actin cytoskeleton remodelling in the podocytes by preserving. The activation of smase has been suggested as a major route for the production of ceramide in response to cellular stresses.
Has in vitro phosphodiesterase activity, but the physiological substrate is unknown pubmed. Crystal structure of the acid sphingomyelinaselike. Regulation of sphingomyelin phosphodiesterase acidlike 3a. Sep 09, 2010 sphingomyelin phosphodiesterase, acid like 3b estimation of enrichment for transcripts expressed in a given population was based on a more than 2fold difference in expression levels determined in 3 independent experiments. We hypothesized that rituximab prevents recurrent fsgs. Diabetes and obesity research program, research programs unit. Smpdl3b, sphingomyelin phosphodiesterase acid like 3b orthology source. Acid sphingomyelinaselike phosphodiesterase 3b imported. A recent study reported that the loss of sphingomyelin phosphodiesterase acid like 3b smpdl 3b in allogeneic human kidney grafts was related to the development of posttransplant proteinuria in patients with focal segmental glomerulosclerosis fsgs 18. Reduction in smpdl3bpositive podocytes was observed in biopsies showing fsgs 34. Smase is a member of the dnase i superfamily of enzymes and is responsible for breaking sphingomyelin down into phosphocholine and ceramide.
Smpdl3b modulates insulin receptor signaling in diabetic kidney. Smpdl3b sphingomyelin phosphodiesterase acid like 3b is a protein coding gene. Rituximab, in addition to binding to cd20, partially prevented the downregulation of the sphingomyelin phosphodiesterase acidlike 3b protein and acid sphingomyelinase in podocytes treated with the sera from patients with recurrent fsgs. Here we report that smpdl3b excess, as observed in podocytes in diabetic. We recently described that sphingomyelin phosphodiesterase acidlike 3b smpdl3b is expressed in podocytes where it modulates acid sphingomyelinase activity and acts as a master modulator of danger signaling. Sphingomyelin phosphodiesterase acidlike 3a smpdl3a is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages mathew traini 1. Lacks activity with phosphocholinecontaining lipids, but can cleave cdpcholine, and can release phosphate from atp and adp in vitro pubmed. Sphingomyelinaselike phosphodiesterase 3b expression. A mutant allele of the swisnf member baf250a determines the. Identification and biochemical characterization of an acid. Rituximab therapy for focal segmental glomerulosclerosis and. It was recently proposed that the effect of rituximab on nephrotic syndrome is not due to b cells but is instead mediated by its offtarget binding to sphingomyelin phosphodiesterase acid like 3b smpdl3b expressed on podocytes. Immunohistochemical analysis detected smpdl3b in glomeruli. Furthermore, several reports identified this enzyme as an off target of the therapeutic antibody rituximab, with implications in kidney disorders.
Second, acid sphingomyelinase like phosphodiesterase 3b encoded by smpdl3b has a role in the conversion of sphingomyelin to ceramide and its levels are reduced in renal biopsy samples from. Second, acid sphingomyelinaselike phosphodiesterase 3b encoded by smpdl3b has a role in the conversion of sphingomyelin to ceramide and its levels are reduced in renal biopsy samples from. Sphingomyelin phosphodiesterase acidlike 3a smpdl3a is a. Sphingomyelin phosphodiesterase is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. A mutant allele of the swisnf member baf250a determines. We recently described that sphingomyelin phosphodiesterase acid like 3b smpdl3b is expressed in podocytes where it modulates acid sphingomyelinase activity and acts as a master modulator of danger signaling. Acid sphingomyelinase asmase is a human enzyme that catalyzes the hydrolysis of sphingomyelin to generate the bioactive lipid ceramide and phosphocholine. Smpdl3a is a major source of nucleotide phosphodiesterase activity secreted by liver x receptorstimulated human macrophages. Smpdl3b acid sphingomyelinaselike phosphodiesterase 3b. Sphingomyelin phosphodiesterase acidlike 3b smpdl3b is a lipid raft. Rituximab and therapeutic plasma exchange in recurrent. Human acid sphingomyelinaselike phosphodiesterase 3b. The lipidmodulating enzyme sphingomyelin phosphodiesterase acidlike 3b smpdl3b is a key determinant of podocyte injury and a known off target of the anticd20 antibody rituximab rtx.
It was recently proposed that the effect of rituximab on nephrotic syndrome is not due to b cells but is instead mediated by its offtarget binding to sphingomyelinphosphodiesteraseacidlike3b smpdl3b expressed on podocytes. The 50kd isoform was detected in lipid raft fractions of membranes prepared from differentiated human podocytes and transfected hek293 cells. Sphingomyelin phosphodiesterase, acidlike 3b estimation of enrichment for transcripts expressed in a given population was based on a more than 2fold difference in expression levels determined in 3 independent experiments. More particularly, the present invention relates to methods for treating or reducing the risk of or preventing diseases caused by or associated with pathogenic bacteria of the gastrointestinal gi tract. Sphingomyelin phosphodiesterase an overview sciencedirect. Western blot analysis detected smpdl3b isoforms with apparent molecular masses of 50 and 40 kd. Reduction in smpdl 3b positive podocytes was observed in biopsies showing fsgs. Jun 19, 2019 sphingomyelin phosphodiesterase acid like 3b smpdl3b is a lipid raft enzyme that regulates plasma membrane pm fluidity. Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible crossreactivity with acid sphingomyelinase like phosphodiesterase 3b precursor. Smase is a member of the dnase i superfamily of enzymes and is responsible for breaking sphingomyelin sm down into phosphocholine and ceramide. Rituximab not only recognizes cd20 on b lymphocytes, but might also bind sphingomyelin phosphodiesterase acidlike 3b smpdl3b protein and regulate acid. Sphingomyelin metabolites, such as ceramide, sphingosine, and sphingosine1phosphate have also gained tremendous interest. Nov 11, 2016 the lipidmodulating enzyme sphingomyelin phosphodiesterase acid like 3b smpdl3b is a key determinant of podocyte injury and a known off target of the anticd20 antibody rituximab rtx.
Asmase deficiency is the underlying cause of the genetic diseases niemannpick type a and b and has been implicated in the onset and progression of a number of other human diseases including cancer, depression, liver, and cardiovascular. Smpdl3b sphingomyelin phosphodiesterase acid like 3b homo sapiens human. Sphingomyelin phosphodiesterase acidlike 3b smpdl3b. It has been suggested that rituximab might treat recurrent fsgs through an unknown mechanism. Jci insight b cellderived il4 acts on podocytes to induce.
Smpdl3b, sphingomyelin phosphodiesterase acidlike 3b. Commensal microbiota modulate gene expression in the skin. Sphingomyelin phosphodiesterase acidlike 3a smpdl3a is one of three members of the acid sphingomyelinase asmaselike enzyme family, which also comprises the founding member asmase encoded by smpd1 and sphingomyelin phosphodiesterase acidlike 3b smpdl3b encoded by smpdl3b. The present invention relates to methods for treating or reducing the risk of or preventing diseases caused by or associated with pathogenic bacteria. Sphingomyelinaselike phosphodiesterase 3b mediates. The current study investigates the role of sphingolipids in radiationinduced podocytopathy. Has lower activity with nucleoside diphosphates, and no activity with nucleoside monophosphates pubmed. Smpdl3b sphingomyelin phosphodiesterase, acidlike 3b. Smpdl3b elisa kit sphingomyelin phosphodiesterase, acid. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in. Sphingomyelinase phosphodiesterase acidlike 3a and 3b smpdl3a and smpdl3b are the two paralogues of acid sphingomyelinase asm. Sphingomyelinaselike phosphodiesterase 3b expression levels determine. Gene ontology go annotations related to this gene include hydrolase activity and sphingomyelin phosphodiesterase activity. Rather than acting on antibody production directly, rituximab might prevent actin cytoskeleton remodelling in the podocytes by preserving sphingolipidrelated en.
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