The splice variant LOXIN inhibits LOX-1 receptor function through hetero-oligomerization.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that plays a central role in the pathogenesis of atherosclerosis. We have recently identified a truncated naturally occurring variant of the human receptor LOX-1, named LOXIN, which lacks part of the C-terminus lectin-like domain. In vivo and in vitro studies support that the new splicing isoform is protective against acute myocardial infarction. The mechanism by which LOXIN exerts its protective role is unknown. In this paper we report studies on the heterologous expression and functional characterization of LOXIN variant in mammalian fibroblasts and human endothelial cells. We found that LOXIN, when expressed in the absence of LOX-1, shows diminished plasma membrane localization and is deficient in ox-LDL ligand binding. When co-transfected with the full-length counterpart LOX-1, the two isoforms interact to form LOX-1 oligomers and their interaction leads to a decrease in the appearance of LOX-1 receptors in the plasma membrane and a marked impairment of ox-LDL binding and uptake. Co-immunoprecipitation studies confirmed the molecular LOX-1/LOXIN interaction and the formation of non-functional hetero-oligomers. Our studies suggest that hetero-oligomerization between naturally occurring isoforms of LOX-1 may represent a general paradigm for regulation of LOX-1 function by its variants.
Biocca
Silvia
S
Department of Neuroscience and Laboratory of Clinical Biochemistry, University of Tor Vergata, Rome, Italy.
Filesi
Ilaria
I
Mango
Ruggiero
R
Maggiore
Luana
L
Baldini
Francesco
F
Vecchione
Lucia
L
Viola
Antonella
A
Citro
Gennaro
G
Federici
Giorgio
G
Romeo
Francesco
F
Novelli
Giuseppe
G
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D019281:Dimerization; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D008077:Lipoproteins, LDL / Q000378:metabolism; D009154:Mutation; D009203:Myocardial Infarction / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D008077:Lipoproteins, LDL; D020033:Protein Isoforms; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein