T granules in human platelets function in TLR9 organization and signaling

• Published in: The Journal of cell biology Vol. 198; no. 4; pp. 561 - 574
• Main Authors: Thon, Jonathan N., Peters, Christopher G., Machlus, Kellie R., Aslam, Rukhsana, Rowley, Jesse, Macleod, Hannah, Devine, Matthew T., Fuchs, Tobias A., Weyrich, Andrew S., Semple, John W., Flaumenhaft, Robert, Italiano, Joseph E.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 20.08.2012; The Rockefeller University Press
• Subjects: Animals; Atherosclerosis - blood; Atherosclerosis - genetics; Atherosclerosis - pathology; Blood platelets; Blood Platelets - physiology; Blood Platelets - ultrastructure; Cell Compartmentation - genetics; Cell Compartmentation - physiology; Cytoplasmic Granules - physiology; Cytoplasmic Granules - ultrastructure; Erythroid Precursor Cells - metabolism; Erythroid Precursor Cells - ultrastructure; Gene expression; Human subjects; Humans; Mice; Platelet Activation - genetics; Platelet Activation - physiology; Proteins; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; T cell receptors; Thrombopoiesis - genetics; Thrombopoiesis - physiology; Toll-Like Receptor 9 - biosynthesis; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - physiology; Up-Regulation - genetics; Vascular diseases
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.201111136

Human and murine platelets (PLTs) variably express toll-like receptors (TLRs), which link the innate and adaptive immune responses during infectious inflammation and atherosclerotic vascular disease. In this paper, we show that the TLR9 transcript is specifically up-regulated during pro-PLT production and is distributed to a novel electron-dense tubular system-related compartment we have named the T granule. TLR9 colocalizes with protein disulfide isomerase and is associated with either VAMP 7 or VAMP 8, which regulates its distribution in PLTs on contact activation (spreading). Preincubation of PLTs with type IV collagen specifically increased TLR9 and CD62P surface expression and augmented oligodeoxynucleotide (ODN) sequestration and PLT clumping upon addition of bacterial/viral ODNs. Collectively, this paper (a) tracks TLR9 to a new intracellular compartment in PLTs and (b) describes a novel mechanism of TLR9 organization and signaling in human PLTs.