Abstract
Objective
The ATP-binding cassette transporter ABCG1 mediates cholesterol efflux from macrophages,
and prevents the progression of macrophage foam-cell formation. Much less is known
about the regulatory mechanism of ABCG1, although its physiological importance is
becoming clearer. Here, we show the role of calpain in ABCG1 degradation.
Methods and results
Purified μ-calpain cleaved ABCG1 in crude membrane fractions prepared from human ABCG1-expressing
HEK293 (ABCG1-HEK) cells. In ABCG1-HEK cells, calpeptin treatment, a calpain inhibitor,
inhibited ABCG1 degradation, and thereby increased the expression and cholesterol
efflux function of ABCG1. Biotinylation study demonstrated greater ABCG1 induction
with calpeptin treatment in cell surface than that in whole cell lysates. Together
with the result that increased ABCG1 expression with calpeptin treatment was observed
under clathrin heavy-chain (CHC) knockdown conditions, where ABCG1 internalization
was prevented, calpain is considered to catalyze ABCG1 cleavage on the plasma membrane.
In mouse peritoneal macrophages as well as in ABCG1-HEK cells, calpeptin treatment
inhibited ABCG1 degradation and enhanced ABCG1 expression, even under CHC-depleted
conditions.
Conclusion
These observations indicate that calpain promotes ABCG1 degradation by cleaving cell
surface-resident ABCG1, and consequently reduces the expression and cholesterol efflux
function of ABCG1. Inhibition of ABCG1 cleavage by calpain could be a novel approach
to suppress the progression of atherosclerosis.
Keywords
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Article info
Publication history
Published online: February 04, 2011
Accepted:
December 28,
2010
Received in revised form:
December 16,
2010
Received:
August 14,
2010
Identification
Copyright
© 2011 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
