Article

Retroendocytosis pathway of ABCA1/apoA-I contributes to HDL formation

Kyoto University, Japan.
Genes to Cells (Impact Factor: 2.81). 03/2009; 14(2):191-204. DOI: 10.1111/j.1365-2443.2008.01261.x
Source: PubMed

ABSTRACT

ATP-binding cassette protein A1 (ABCA1) mediates transfer of cellular free cholesterol and phospholipids to apolipoprotein A-I (apoA-I), an extracellular acceptor in plasma, to form high-density lipoprotein (HDL). It is currently unknown to what extent ABCA1 endocytosis and recycling contribute to the HDL formation. To address this issue, we expressed human ABCA1 constructs with either an extracellular HA tag or an intracellular GFP tag in cells, and used this system to characterize endocytosis and recycling of ABCA1 and apoA-I. Under basal conditions, ABCA1 and apoA-I are endocytosed via a clathrin- and Rab5-mediated pathway and recycled rapidly back to the cell surface, at least in part via a Rab4-mediated route; approximately 30% of the endocytosed ABCA1 is recycled back to the cell surface. When receptor-mediated endocytosis is inhibited, the level of ABCA1 at the cell surface increases and apoA-I internalization is blocked. Under these conditions, apoA-I mediated cholesterol efflux from cells that have accumulated lipoprotein-derived cholesterol is decreased, whereas efflux from cells without excess cholesterol is increased. These results suggest that the retroendocytosis pathway of ABCA1/apoA-I contributes to HDL formation when excess lipoprotein-derived cholesterol has accumulated in cells.

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Available from: Hye-Won Shin, Sep 10, 2014
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    • "A candidate protein that could be involved in this process is Rab4, one of several small GTP binding proteins recruited to the inclusion membrane of C. trachomatis-infected cells (Rzomp et al., 2003; 2006; Moorhead et al., 2010). ABCA1 normally undergoes internalization from the plasma membrane and recycles from endosomes back to the cell surface in a Rab4-dependent fashion (Neufeld et al., 2001; Azuma et al., 2009). Whether C. trachomatis infection alters Rab4 function resulting in the recruitment of ABCA1 and apoA-1, which associates with ABCA1 (Wang et al., 2000), to the inclusion of infected cells is currently under investigation. "
    Dataset: Cox et al

    Full-text · Dataset · Jan 2014
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    • "A candidate protein that could be involved in this process is Rab4, one of several small GTP binding proteins recruited to the inclusion membrane of C. trachomatis-infected cells (Rzomp et al., 2003; 2006; Moorhead et al., 2010). ABCA1 normally undergoes internalization from the plasma membrane and recycles from endosomes back to the cell surface in a Rab4-dependent fashion (Neufeld et al., 2001; Azuma et al., 2009). Whether C. trachomatis infection alters Rab4 function resulting in the recruitment of ABCA1 and apoA-1, which associates with ABCA1 (Wang et al., 2000), to the inclusion of infected cells is currently under investigation. "
    Dataset: Cox et al

    Full-text · Dataset · Sep 2013
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    • "A candidate protein that could be involved in this process is Rab4, one of several small GTP binding proteins recruited to the inclusion membrane of C. trachomatis-infected cells (Rzomp et al., 2003; 2006; Moorhead et al., 2010). ABCA1 normally undergoes internalization from the plasma membrane and recycles from endosomes back to the cell surface in a Rab4-dependent fashion (Neufeld et al., 2001; Azuma et al., 2009). Whether C. trachomatis infection alters Rab4 function resulting in the recruitment of ABCA1 and apoA-1, which associates with ABCA1 (Wang et al., 2000), to the inclusion of infected cells is currently under investigation. "
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    ABSTRACT: Chlamydia trachomatis is an obligate intracellular bacterial pathogen that is the most common cause of sexually transmitted bacterial infections and is the etiological agent of trachoma, the leading cause of preventable blindness. The organism infects epithelial cells of the genital tract and eyelid resulting in a damaging inflammatory response. Chlamydia trachomatis grows within a vacuole termed the inclusion, and its growth depends on numerous host factors, including lipids. Although a variety of mechanisms are involved in the acquisition of host cell cholesterol and glycosphingolipids by C. trachomatis, none of the previously documented pathways for lipid acquisition are absolutely required for growth. Here we demonstrate that multiple components of the host high-density lipoprotein (HDL) biogenesis machinery including the lipid effluxers, ABCA1 and CLA 1, and their extracellular lipid acceptor, apoA-1, are recruited to the inclusion of C. trachomatis-infected cells. Furthermore, the apoA-1 that accumulates within the inclusion colocalizes with pools of phosphatidylcholine. Knockdown of ABCA1, which mediates the cellular efflux of cholesterol and phospholipids to initiate the formation of HDL in the serum, prevents the growth of C. trachomatis in infected HeLa cells. In addition, drugs that inhibit the lipid transport activities of ABCA1 and CLA 1 also inhibit the recruitment of phospholipids to the inclusion and prevent chlamydial growth.These results strongly suggest that C. trachomatis co-opts the host cell lipid transport system involved in the formation of HDL to acquire lipids, such as phosphatidylcholine, that are necessary for growth.
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