Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 3, Pages 1355-1363Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.524561
Keywords
ATPases; Dendritic Cells; Proton Pumps; Transport; Vacuolar Acidification; Vacuolar ATPase; Regulated V-ATPase Assembly
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Funding
- National Institutes of Health [GM34478]
- NIAID [RO1 18919]
- Sackler Dean's Fellow award
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Background: The V-ATPase is induced to assemble during TLR-activated maturation of dendritic cells. Results: Cluster disruption of dendritic cells also induces V-ATPase assembly by a PI3K/mTOR-dependent mechanism. Conclusion: Semi-mature dendritic cells show increased V-ATPase assembly. Significance: Dendritic cell maturation associated with immune tolerance involves V-ATPase assembly. The vacuolar (H+)-ATPases (V-ATPases) are ATP-driven proton pumps composed of a peripheral V-1 domain and a membrane-embedded V-0 domain. Regulated assembly of V-1 and V-0 represents an important regulatory mechanism for controlling V-ATPase activity in vivo. Previous work has shown that V-ATPase assembly increases during maturation of bone marrow-derived dendritic cells induced by activation of Toll-like receptors. This increased assembly is essential for antigen processing, which is dependent upon an acidic lysosomal pH. Cluster disruption of dendritic cells induces a semi-mature phenotype associated with immune tolerance. Thus, semi-mature dendritic cells are able to process and present self-peptides to suppress autoimmune responses. We have investigated V-ATPase assembly in bone marrow-derived, murine dendritic cells and observed an increase in assembly following cluster disruption. This increased assembly is not dependent upon new protein synthesis and is associated with an increase in concanamycin A-sensitive proton transport in FITC-loaded lysosomes. Inhibition of phosphatidylinositol 3-kinase with wortmannin or mTORC1 with rapamycin effectively inhibits the increased assembly observed upon cluster disruption. These results suggest that the phosphatidylinositol 3-kinase/mTOR pathway is involved in controlling V-ATPase assembly during dendritic cell maturation.
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