Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01687-x
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Funding
- RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan [RBRC00850]
- Collaborative Research Grant from Daiichi Sankyo Co. Ltd.
- Institute of Medical Science, the University of Tokyo
- Takeda Science Foundation
- [25253032]
- [16H06388]
- [26293083]
- Grants-in-Aid for Scientific Research [26291038, 17K19548, 17K07351, 16H06388, 26293083, 16K15253, 16H06578, 16H05193] Funding Source: KAKEN
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Plasmacytoid dendritic cells (pDC) sense viral RNA through toll-like receptor 7 (TLR7), form self-adhesive pDC-pDC clusters, and produce type I interferons. This cell adhesion enhances type I interferon production, but little is known about the underlying mechanisms. Here we show that MyD88-dependent TLR7 signaling activates CD11a/CD18 integrin to induce microtubule elongation. TLR7+ lysosomes then become linked with these microtubules through the GTPase Arl8b and its effector SKIP/Plekhm2, resulting in perinuclear to peripheral relocalization of TLR7. The type I interferon signaling molecules TRAF3, IKK alpha, and mTORC1 are constitutively associated in pDCs. TLR7 localizes to mTORC1 and induces association of TRAF3 with the upstream molecule TRAF6. Finally, type I interferons are secreted in the vicinity of cell-cell contacts between clustered pDCs. These results suggest that TLR7 needs to move to the cell periphery to induce robust type I interferon responses in pDCs.
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