Abstract
SR-A (class A macrophage scavenger receptor) is a transmembrane receptor that can bind many different ligands, including modified lipoproteins that are relevant to the development of vascular diseases. However, the precise endocytic pathways of SR-A/mediated ligands internalization are not fully characterized. In this study, we show that the SR-A/ligand complex can be endocytosed by both clathrin- and caveolae-dependent pathways. Internalizations of SR-A-lipoprotein (such as acLDL) complexes primarily go through clathrin-dependent endocytosis. In contrast, macrophage apoptosis triggered by SR-A-fucoidan internalization requires caveolae-dependent endocytosis. The caveolae-dependent process activates p38 kinase and JNK signaling, whereas the clathrin-mediated endocytosis elicits ERK signaling. Our results suggest that different SR-A endocytic pathways have distinct functional consequences due to the activation of different signaling cascades in macrophages.
Highlights
Our previous results showed a direct interaction between SR-A and clathrin [14], which was further confirmed by a coimmunoprecipitation assay in this study (Fig. 1A)
Taken together with the results that caveolae- but not clathrin-mediated endocytosis is the primary pathway for the SR-A-fucoidan-induced p38 kinase and JNK activation, our study provides a cellular pathway selectively required for SR-A-dependent apoptosis in endoplasmic reticulum stressed macrophages
We found that the distinct endocytic pathways of SR-A are independent on the concentration of ligand
Summary
Clathrin-dependent endocytosis is the most well characterized mechanism for mediating the internalization of membrane receptors into cells. The caveolae-dependent pathway is required for p38 kinase and JNK signaling as well as caspase activation. Our results indicate for the first time that SR-A-mediated macrophage apoptosis may be selectively regulated by the caveolae-dependent endocytosis.
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