Major vault protein regulates class A scavenger receptor-mediated TNF-α synthesis and apoptosis in macrophages.

Atherosclerosis is considered a disease of chronic inflammation largely initiated and perpetuated by macrophage-dependent synthesis and release of pro-inflammatory mediators. Class A scavenger receptor (SR-A) expressed on macrophages plays a key role in this process. However, how SR-A mediated pro-inflammatory response is modulated in macrophages remains ill-defined. Here through immunoprecipitation coupled with mass spectrometry, we reported major vault protein (MVP) as a novel binding partner for SR-A. The interaction between SR-A and MVP was confirmed by immunofluorescence staining and chemical crosslinking assay. Treatment of macrophages with fucoidan, a SR-A ligand, led to a marked increase in TNF-alpha production, which was attenuated by MVP depletion. Further analysis revealed that SR-A stimulated TNF-alpha synthesis in macrophages via the caveolin- instead of clathrin-mediated endocytic pathway linked to p38- and JNK-, but not ERK-, signaling pathways. Importantly, fucoidan invoked an enrichment of MVP in lipid raft, a caveolin-reliant membrane structure, and enhanced the interaction between SR-A, caveolin, and MVP. Finally, we demonstrated that MVP elimination ameliorated SR-A-mediated apoptosis in macrophages. As such, MVP may fine-tune SR-A activity in macrophages and by which contributes to the development of atherosclerosis.