A unique lysophospholipid acyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways

Chambers, Kimberly; Judson, Bret L.; Brown, William J.

doi:10.1242/jcs.02435

Cited by 32 publications

(23 citation statements)

References 45 publications

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“…However, recent results question the importance of the acyltransferase activity of endophilin and CtBP/BARS in the formation of transport vesicles (Gallop et al, 2005). Alternatively, it is very interesting that the compound CI-976, a potent lysophospholipid acyltransferase inhibitor, has been reported to block transport of both the transferrin receptor from the ERC to the plasma membrane as well as Golgi transport (Chambers et al, 2005). Other models are also consistent with our results.…”

Section: Discussionsupporting

confidence: 89%

MAA-1, a Novel Acyl-CoA–binding Protein Involved in Endosomal Vesicle Transport inCaenorhabditis elegans

Kobæk-Larsen

Tuck

Færgeman

et al. 2006

MBoC

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The budding and fission of vesicles during membrane trafficking requires many proteins, including those that coat the vesicles, adaptor proteins that recruit components of the coat, and small GTPases that initiate vesicle formation. In addition, vesicle formation in vitro is promoted by the hydrolysis of acyl-CoA lipid esters. The mechanisms by which these lipid esters are directed to the appropriate membranes in vivo, and their precise roles in vesicle biogenesis, are not yet understood. Here, we present the first report on membrane associated ACBP domain-containing protein-1 (MAA-1), a novel membrane-associated member of the acyl-CoA-binding protein family. We show that in Caenorhabditis elegans, MAA-1 localizes to intracellular membrane organelles in the secretory and endocytic pathway and that mutations in maa-1 reduce the rate of endosomal recycling. A lack of maa-1 activity causes a change in endosomal morphology. Although in wild type, many endosomal organelles have long tubular protrusions, loss of MAA-1 activity results in loss of the tubular domains, suggesting the maa-1 is required for the generation or maintenance of these domains. Furthermore, we demonstrate that MAA-1 binds fatty acyl-CoA in vitro and that this ligand-binding ability is important for its function in vivo. Our results are consistent with a role for MAA-1 in an acyl-CoA-dependent process during vesicle formation.

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Section: Discussionsupporting

confidence: 89%

MAA-1, a Novel Acyl-CoA–binding Protein Involved in Endosomal Vesicle Transport inCaenorhabditis elegans

Kobæk-Larsen

Tuck

Færgeman

et al. 2006

MBoC

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“…Our previous studies have revealed a novel role for LPATs, and specifically AGPAT3/LPAAT3, in regulating the structure and function of the Golgi complex [7,22,23]. AGPAT3/LPAAT3 appears to negatively regulate the formation of Golgi membrane tubules that likely serve as trafficking intermediates for plasma membrane delivery and for maintenance of an intact Golgi ribbon.…”

Section: Resultsmentioning

confidence: 99%

Membrane topology of human AGPAT3 (LPAAT3)

Schmidt¹,

Yvone²,

Brown³

2010

Biochemical and Biophysical Research Communications

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Integral membrane lysophospholipid acyltransferases (AT) are involved in many reactions that produce phospholipids and triglycerides. Enzymes that utilize lysophosphatidic acid (LPA) as an acceptor substrate have been termed LPAATs, and several are members of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) gene family. Amino acid sequence comparisons with other acyltransferases reveal that AGPATs contain four conserved motifs (I–IV), whose invariant residues appear to be important for catalysis and/or substrate recognition. Although the enzymatic activities of many AGPATs are known, for many members their structural organization within membranes and their exact biological functions are unclear. Recently, a new function for AGPATs was discovered when it was determined that human AGPAT3/LPAAT3 is involved in the structure and function of the Golgi complex. Here we have determined the topological orientation of human AGPAT3/LPAAT3. AGPAT3/LPAAT3 possesses two transmembrane domains, one of which separates motifs I and II, which are thought to form a functional unit that is critical for enzymatic activity. This is a surprising result but similar to a recent study on the topology of human LPAAT 1. The data is consistent with a structural arrangement in which motif I is located in the cytoplasm and motif II is in the endoplasmic reticulum and Golgi lumen, suggesting a different model for AGPAT3/LPAAT3’s enzymatic mechanism.

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“…6A). CI-976, a small, hydrophobic, membrane-permeant compound which inhibits COP II vesicle budding from the ER (Chambers and Brown, 2004; Chambers et al, 2005), reduced cell viability by more than 50% relative to control cells ( p <0.0001), while CytoD, a fungal metabolite that inhibits actin polymerization in the cell cytoskeleton (Ramm et al, 1994), reduced viability by 25% ( p <0.0006; Fig. 6B).…”

Section: Resultsmentioning

confidence: 99%

Iron loaded ferritin secretion and inhibition by CI-976 in Aedes aegypti larval cells

Geiser¹,

Shen²,

Mayo³

et al. 2009

Comparative Biochemistry and Physiology Part B: Biochemistry an

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Ferritin is a multimer of 24 subunits of heavy and light chains. In mammals, iron taken into cells is stored in ferritin or incorporated into iron-containing proteins. Very little ferritin is found circulating in mammalian serum; most is retained in the cytoplasm. Female mosquitoes, such as Aedes aegypti (yellow fever mosquito, Diptera), require a blood meal for oogenesis. Mosquitoes receive a potentially toxic level of iron in the blood meal which must be processed and stored. We demonstrate by 59Fe pulse-chase experiments that cultured A. aegypti larval CCL-125 cells take up iron from culture media and store it in ferritin found mainly in the membrane fraction and secrete iron-loaded ferritin. We observe that in these larval cells ferritin co-localizes with ceramide-containing membranes in the absence of iron. With iron treatment, ferritin is found associated with ceramide-containing membranes as well as in cytoplasmic non-ceramide vesicles. Treatment of CCL-125 cells with iron and CI-976, an inhibitor of lysophospholipid acyl transferases, disrupts ferritin secretion with a concomitant decrease in cell viability. Interfering with ferritin secretion may limit the ability of mosquitoes to adjust to the high iron load of the blood meal and decrease iron delivery to the ovaries reducing egg numbers.

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A unique lysophospholipid acyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways

Cited by 32 publications

References 45 publications

MAA-1, a Novel Acyl-CoA–binding Protein Involved in Endosomal Vesicle Transport inCaenorhabditis elegans

MAA-1, a Novel Acyl-CoA–binding Protein Involved in Endosomal Vesicle Transport inCaenorhabditis elegans

Membrane topology of human AGPAT3 (LPAAT3)

Iron loaded ferritin secretion and inhibition by CI-976 in Aedes aegypti larval cells

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