title: Major vault protein regulates class A scavenger receptor-mediated tumor necrosis factor-α synthesis and apoptosis in macrophages.
abstract: 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 cross-linking assay. Treatment of macrophages with fucoidan, a SR-A ligand, led to a marked increase in TNF-α production, which was attenuated by MVP depletion. Further analysis revealed that SR-A stimulated TNF-α 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 among 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 which contributes to the development of atherosclerosis.
authors.affiliation: Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ben
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rongmei
authors.initials: R
authors.lastname: Zhou
authors.forename: Haiyang
authors.initials: H
authors.lastname: Zhang
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhu
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Zhou
authors.forename: Hui
authors.initials: H
authors.lastname: Bai
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Donghai
authors.initials: D
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D022461:Caveolins / Q000378:metabolism; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D021962:Membrane Microdomains; D051379:Mice; D011134:Polysaccharides / Q000494:pharmacology; D051117:Scavenger Receptors, Class A / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*; D000099187:Major Vault Protein
chemical_list: D000970:Antineoplastic Agents; D022461:Caveolins; D002966:Clathrin; D011134:Polysaccharides; D051117:Scavenger Receptors, Class A; D014409:Tumor Necrosis Factor-alpha; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C495140:Msr1 protein, mouse; C007789:fucoidan
keywords: Apoptosis; Caveolae; Macrophages; Major Vault Protein; Scavenger Receptor; Tumor Necrosis Factor (TNF)