Mutation in AP-3 δ in the mocha Mouse Links Endosomal Transport to Storage Deficiency in Platelets, Melanosomes, and Synaptic Vesicles

Kantheti, Prameela; Qiao, Xuguang; Díaz, María Alejandra; Peden, Andrew A.; Meyer, Gary; Carskadon, Shannon; Kaufholdt, David; Sufalko, Damaris; Robinson, Margaret S.; Noebels, Jeffrey L.; Burmeister, Margit

doi:10.1016/s0896-6273(00)80519-x

Cited by 381 publications

(434 citation statements)

References 52 publications

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“…29 AP3 is a heterotetrameric adaptor protein involved in the biogenesis of lysosome-related organelles, such as platelet-dense bodies. The 'mocha' mouse mutant with a null allele of Ap3d1 shows bleeding abnormalities due to the storage pool deficiency in the dense granules of platelets, 30 raising the possibility that AP3D1 functions as the modulator of thrombogenesis via platelet function.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

et al. 2014

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Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210:A4G, P ¼ 2.60 Â 10 À9 , odds ratio (OR) ¼ 0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915:A4C, P ¼ 3.84 Â 10 À9 , OR ¼ 0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886:A4G: P ¼ 1.14 Â 10 À14 , OR ¼ 1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci. INTRODUCTIONMyocardial infarction (MI), the severest form of coronary artery disease (CAD), is characterized by the occlusion of the coronary artery, resulting in ischemic damage of the myocardium. The occlusion of the coronary artery is characterized by abrupt plaque rupture with thrombogenesis 1 following the atherosclerotic process, which has recently been regarded as a chronic inflammatory condition involving lipid accumulation, abnormal extracellular matrix metabolism, innate immunity with macrophages, and the adaptive immune response with T and B lymphocytes. 2 Despite recent dramatic advances in preventive and/or therapeutic strategies, MI is still one of the leading causes of death in Asian populations as well as European populations.The pathogenesis of MI is considered to be the cumulative effect of multiple genetic and environmental factors. For the genetic aspect, a

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Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

et al. 2014

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“…In vitro studies have demonstrated that SVs can be budded from the endosomal compartment with the use of AP-3 and the small GTPase ADP ribosylation factor 1 (Faundez et al, 1997 as well as being brefeldin A-sensitive (Shi et al, 1998). However, AP-3 ␦ subunit mutants in mouse are viable and contain an abundance of normal SVs, suggesting this is not an obligate pathway (Kantheti et al, 1998). In addition, recent data have documented that a third route of SLMV formation, from the late endosome, also exists in PC12 cells.…”

Section: Synaptic Localization Signals In Other Systemsmentioning

confidence: 99%

A Conserved Mechanism of Synaptogyrin Localization

Zhao

Nonet

2001

MBoC

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We have studied the localization of synaptogyrin family members in vivo. Both native and green fluorescent protein (GFP)-tagged Caenorhabditis elegans synaptogyrin (SNG-1) are expressed in neurons and synaptically localized. Deletion and mutational analysis with the use of GFP-tagged SNG-1 has defined a 38 amino acid sequence within the C terminus of SNG-1 and a single arginine in the cytoplasmic loop between transmembrane domain 2 and 3 that are required for SNG-1 localization. These domains may represent components of signals that target synaptogyrin for endocytosis from the plasma membrane and direct synaptogyrin to synaptic vesicles, respectively. In chimeric studies, these regions were sufficient to relocalize cellugyrin, a nonneuronal form of synaptogyrin, from nonsynaptic regions such as the sensory dendrites and the cell body to synaptic vesicles. Furthermore, GFP-tagged rat synaptogyrin is synaptically localized in neurons of C. elegans and in cultured hippocampal neurons. Similarly, the C-terminal domain of rat synaptogyrin is necessary for localization in hippocampal neurons. Our study suggests that the mechanisms for synaptogyrin localization are likely to be conserved from C. elegans to vertebrates. INTRODUCTIONSynaptic vesicles (SVs) contain a restricted set of membrane proteins important for neuronal function (Sü dhof, 1995;Calakos and Scheller, 1996;Fernandez-Chacon and Sü dhof, 1999). The mechanisms responsible for targeting these proteins specifically to the SV membrane are poorly understood. Integral membrane proteins are synthesized on the rough endoplasmic reticulum and traffic through the Golgi network. Proteins exiting the trans-Golgi network (TGN) are sorted to different types of transport vesicles. SV proteins are sorted to synaptic vesicle precursors (preSVs), which differ from mature SVs both in morphology and protein composition (Tsukita and Ishikawa, 1980; Okada et al., 1995). Evidence supports both direct routing of SV proteins from TGN to preSVs and indirect routing via the plasma membrane (reviewed by Hannah et al., 1999). preSVs are subsequently transported along axonal processes to the nerve terminal by motor proteins of the kinesin superfamily (reviewed by Hirokawa, 1998). How preSVs mature after delivery to the nerve terminal is unknown. preSVs might fuse with an endosomal compartment and SVs generated by budding from the endosome. A second, but not mutually exclusive possibility, is that preSVs are delivered to the presynaptic plasma membrane at the nerve terminal and then retrieved by the same mechanism(s) used to recycle SVs after regulated exocytosis (Hannah et al., 1999; reviewed by Buckley et al., 2000). Regardless of the exact route of trafficking to the mature organelle, SV proteins must be sorted away from other membrane proteins at several stages during their life cycle.Signal sequences resident in proteins are thought to mediate the sorting of many proteins to cellular compartments. Several studies have identified domains and motifs necessary for correct localizati...

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“…Recently, another ubiquitously expressed adaptor-related complex, AP-3, was described (Simpson et al, 1996(Simpson et al, , 1997Dell'Angelica et al, 1997) and shown to be involved in the delivery of proteins to lysosomes and lysosome-related organelles, including the yeast vacuole (Cowles et al, 1997;Panek et al, 1997) and insect and mammalian pigment granules (Dell'Angelica et al, 1997;Simpson et al, 1997;Kantheti et al, 1998). Conflicting results have been obtained as to whether the AP-3 complex is associated with clathrin.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Fourth Adaptor-related Protein Complex

Hirst

Bright

Rous

et al. 1999

MBoC

289

273

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Adaptor protein complexes (APs) function as vesicle coat components in different membrane traffic pathways; however, there are a number of pathways for which there is still no candidate coat. To find novel coat components related to AP complexes, we have searched the expressed sequence tag database and have identified, cloned, and sequenced a new member of each of the four AP subunit families. We have shown by a combination of coimmunoprecipitation and yeast two-hybrid analysis that these four proteins (⑀, ␤4, 4, and 4) are components of a novel adaptor-like heterotetrameric complex, which we are calling AP-4. Immunofluorescence reveals that AP-4 is localized to ϳ10 -20 discrete dots in the perinuclear region of the cell. This pattern is disrupted by treating the cells with brefeldin A, indicating that, like other coat proteins, the association of AP-4 with membranes is regulated by the small GTPase ARF. Immunogold electron microscopy indicates that AP-4 is associated with nonclathrin-coated vesicles in the region of the trans-Golgi network. The 4 subunit of the complex specifically interacts with a tyrosine-based sorting signal, indicating that, like the other three AP complexes, AP-4 is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs. AP-4 is of relatively low abundance, but it is expressed ubiquitously, suggesting that it participates in a specialized trafficking pathway but one that is required in all cell types.

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Mutation in AP-3 δ in the mocha Mouse Links Endosomal Transport to Storage Deficiency in Platelets, Melanosomes, and Synaptic Vesicles

Cited by 381 publications

References 52 publications

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

A Conserved Mechanism of Synaptogyrin Localization

Characterization of a Fourth Adaptor-related Protein Complex

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