Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release

doi:10.1016/j.bbrc.2003.10.002

Biochemical and Biophysical Research Communications

Volume 311, Issue 2, 14 November 2003, Pages 313-318

https://doi.org/10.1016/j.bbrc.2003.10.002 Get rights and content

Abstract

ABCA7 is expressed predominantly in myelo-lymphatic tissues or reticuloendothelial cells. Physiological role and function of this protein are not fully understood. We isolated the full-length cDNA (type I) and a splicing variant cDNA (type II) of human ABCA7, and developed monoclonal antibodies against extracellular domain (ECD)1 of ABCA7. RT-PCR experiments suggested that human ABCA7 gene produced the type II mRNA in a tissue-specific manner. Immunostaining revealed that the type I ABCA7, expressed in HEK293 cells, was localized to the plasma membrane and ECD1 was exposed to the extracellular space as was the case for ABCA1. HEK293 cells expressing type I ABCA7 showed apoA-I-dependent cholesterol and phospholipid release. In contrast, type II ABCA7 appeared to be localized mainly in endoplasmic reticulum and did not show apoA-I-dependent cholesterol and phospholipid release. Alternative splicing could be involved in the post-transcriptional regulation of the expression and function of human ABCA7.

Section snippets

Materials and methods

Materials. Anti-GFP antibody was purchased from Santa Cruz Biotechnology. All other chemicals were obtained from Sigma, Wako Pure Chemical Industries or Nacalai Tesque.

Generation of antibodies to ABCA7 ECD1. The putative extracellular domain ECD1, amino acids 45–549 of human ABCA7, was cloned into the pGEX4T-3 vector (Amersham–Pharmacia Biotech) and expressed as a fusion protein with glutathione-S-transferase. The fusion protein was purified by glutathione–Sepharose 4B chromatography

Expression of a splicing variant of ABCA7

We previously reported that the ECD1 of ABCA1 contains a segment homologous to the autoantigen SS-N, an epitope of Sjögren’s syndrome, and that the Kazusa human brain cDNA clone hh10210 also contains the sequence [15]. This gene had also been described as a human sterol-sensitive ABC transporter ABCA7 by Kaminski et al. [16]. However, the clone hh10210 contained an extra 348-base sequence, which did not exist in the sequence reported as human ABCA7 cDNA [16]. Here we called the 348-base region

Discussion

ABCA7 is an ATP-binding cassette (ABC) transporter that is most highly homologous to ABCA1 among human ABC proteins and reportedly expressed predominantly in myelo-lymphatic tissues. Physiological function of this protein was not fully understood. In this study, we attempted to investigate post-transcriptional regulation of expression of this protein in relation to its function. We isolated the full-length cDNA (type I) and a splicing variant cDNA (type II) of human ABCA7 and developed

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.

References (24)

Y.K. Ho et al.
Hydrolysis and excretion of cytoplasmic cholesterol esters by macrophages: stimulation by high density lipoprotein and other agents
J. Lipid Res.
(1980)
S. Yokoyama
Release of cellular cholesterol: molecular mechanism for cholesterol homeostasis in cells and in the body
Biochim. Biophys. Acta
(2000)
M. Marcil et al.
Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux
Lancet
(1999)
M.E. Brousseau et al.
Novel mutations in the gene encoding ATP-binding cassette1 in four Tangier disease kindreds
J. Lipid Res.
(2000)
M.L. Fitzgerald et al.
Naturally occurring mutations in ABCA1’s largest extracellular loops can disrupt its direct interaction with apolipoprotein A-I
J. Biol. Chem.
(2002)
V. Rigot et al.
Distinct sites on ABCA1 control distinct steps required for cellular release of phospholipids
J. Lipid Res.
(2002)
A.R. Tanaka et al.
Effects of mutations of ABCA1 in the first extracellular domain on subcellular trafficking and ATP binding/hydrolysis
J. Biol. Chem.
(2003)
A.R. Tanaka et al.
Human ABCA1 contains a large amino-terminal extracellular domain homologous to an epitope of sjogren’s syndrome
Biochem. Biophys. Res. Commun.
(2001)
W. Kaminski et al.
Identification of a novel human sterol-sensitive ATP-binding cassette transporter (ABCA7)
Biochem. Biophys. Res. Commun.
(2000)
M.L. Fitzgerald et al.
ABCA1 contains an N-terminal signal-anchor sequence that translocates the protein’s first hydrophilic domain to the exoplasmic space
J. Biol. Chem.
(2001)

E.B. Neufeld et al.

Cellular localization and trafficking of the human ABCA1 transporter

J. Biol. Chem.

(2001)

A.T. Remaley et al.

Apolipoprotein specificity for lipid efflux by the human ABCAI transporter

Biochem. Biophys. Res. Commun.

(2001)

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Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release

Abstract

Section snippets

Materials and methods

Expression of a splicing variant of ABCA7

Discussion

Acknowledgements

J. Lipid Res.

Biochim. Biophys. Acta

Lancet

J. Lipid Res.

J. Biol. Chem.

J. Lipid Res.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.