Goodpasture Antigen-binding Protein/Ceramide Transporter Binds to Human Serum Amyloid P-Component and Is Present in Brain Amyloid Plaques

Mencarelli, Chiara; Bode, Gerard H.; Losen, Mario; Kulharia, Mahesh; Molenaar, Peter; Veerhuis, Robert; Steinbusch, Harry W.M.; Baets, Marc H. De; Nicolaes, Gerry A. F.; Martínez‐Martínez, Pilar

doi:10.1074/jbc.m111.299545

Cited by 40 publications

(81 citation statements)

References 48 publications

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“…For example, Alzheimer's disease is characterized by extensive complement activation in the brain (51). In fact, we observed CERT L associated with activated microglia in brain amyloid plaques of Alzheimer's disease patients (18). Moreover, microglia in Alzheimer's disease brain secrete proinflammatory cytokines, including TNF-a (52), which could drive CERT L expression.…”

Section: Discussionmentioning

confidence: 81%

“…This interaction between SAP and CERT L was inhibited by C1q (18), prompting us to investigate the relationship between these proteins in more detail. Binding of C1q to immobilized CERT L and CERT was observed by ELISA, whereas C1q did not bind to BSA, which was used as negative control (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We recently identified the ceramide transporter proteins (CERTs) as ligands for SAP and found that this interaction was inhibited by C1q (18). Several isoforms of CERT proteins exist and are present in various tissues and in blood (18)(19)(20).…”

mentioning

confidence: 99%

“…Several isoforms of CERT proteins exist and are present in various tissues and in blood (18)(19)(20). The shorter splicing isoform CERT is ubiquitously present inside the cell and functions as a carrier for ceramide between the endoplasmic reticulum and the Golgi apparatus (19,21).…”

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confidence: 99%

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Complement Activation by Ceramide Transporter Proteins

Bode

Losen

Buurman

et al. 2014

The Journal of Immunology

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C1q is the initiator of the classical complement pathway and, as such, is essential for efficient opsonization and clearance of pathogens, altered self-structures, and apoptotic cells. The ceramide transporter protein (CERT) and its longer splicing isoform CERTL are known to interact with extracellular matrix components, such as type IV collagen, and with the innate immune protein serum amyloid P. In this article, we report a novel function of CERT in the innate immune response. Both CERT isoforms, when immobilized, were found to bind the globular head region of C1q and to initiate the classical complement pathway, leading to activation of C4 and C3, as well as generation of the membrane attack complex C5b–9. In addition, C1q was shown to bind to endogenous CERTL on the surface of apoptotic cells. These results demonstrate the role of CERTs in innate immunity, especially in the clearance of apoptotic cells.

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Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Complement Activation by Ceramide Transporter Proteins

Bode

Losen

Buurman

et al. 2014

The Journal of Immunology

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“…However, observations of the dynamic distribution of peroxidasin in BMs is limited to development of C. elegan tissues [31] and cell lines [32], and has been implied in embryonic mouse tissues [29]. Extracellular GPBP was discovered through its binding to kidney BM [33] and has since been shown to bind major BM components laminin and collagen IV [34,35]. Overexpression of GPBP in renal tissues is associated with collagen IV rearrangement and ultrastructure expansion of glomerular BM in immune complex-mediated pathogenesis in mice and humans [36,37].…”

Section: Introductionmentioning

confidence: 99%

Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming

et al. 2017

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Basement membranes (BMs) are specialized extracellular scaffolds that influence behaviors of cells in epithelial, endothelial, muscle, nervous, and fat tissues. Throughout development and in response to injury or disease, BMs are fine-tuned with specific protein compositions, ultrastructure, and localization. These features are modulated through implements of the BM toolkit that is comprised of collagen IV, laminin, perlecan, and nidogen. Two additional proteins, peroxidasin and Goodpasture antigen-binding protein (GPBP), have recently emerged as potential members of the toolkit. In the present study, we sought to determine whether peroxidasin and GPBP undergo dynamic regulation in the assembly of uterine tissue BMs in early pregnancy as a tractable model for dynamic adult BMs. We explored these proteins in the context of collagen IV and laminin that are known to extensively change for decidualization. Electron microscopic analyses revealed: 1) a smooth continuous layer of BM in between the epithelial and stromal layers of the preimplantation endometrium; and 2) interrupted, uneven, and progressively thickened BM within the pericellular space of the postimplantation decidua. Quantification of mRNA levels by qPCR showed changes in expression levels that were complemented by immunofluorescence localization of peroxidasin, GPBP, collagen IV, and laminin. Novel BM-associated and subcellular spatiotemporal localization patterns of the four components suggest both collective pericellular functions and distinct functions in the uterus during reprogramming for embryo implantation.

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Asymmetric Synthesis and Binding Study of New Long‐Chain HPA‐12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

Ďuriš

Daı̈ch

Santos

et al. 2016

Chemistry A European J

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A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.

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Goodpasture Antigen-binding Protein/Ceramide Transporter Binds to Human Serum Amyloid P-Component and Is Present in Brain Amyloid Plaques

Cited by 40 publications

References 48 publications

Complement Activation by Ceramide Transporter Proteins

Complement Activation by Ceramide Transporter Proteins

Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming

Asymmetric Synthesis and Binding Study of New Long‐Chain HPA‐12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

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