Submitted December 11, 2008
Accepted June 2, 2009
Spatiotemporal regulation of intracellular trafficking of TLR9 by an inhibitory receptor, Ly49Q
Mariko Yoshizaki, Aya Tazawa, Eiji Kasumi, Shigemi Sasawatari, Kenji Itoh, Taeko Dohi, Takehiko Sasazuki, Kayo Inaba, Andrew P. Makrigiannis, and Noriko Toyama-Sorimachi*
Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan
Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, University of Tokyo, Tokyo, Japan
International Medical Center of Japan, Tokyo, Japan
Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University and JST CREST, Kyoto, Japan
Laboratory of Molecular Immunology, Institute de Recherches Cliniques de Montreal (IRCM), Montreal, QC, Canada
* Corresponding author; email: nsorima{at}ri.imcj.go.jp.
Toll like receptor (TLR) 9 recognizes unmethylated microorganismal CpG DNA and elicits innate immune responses. However, the regulatory mechanisms of the TLR signaling remain elusive. We recently reported that Ly49Q, an ITIM-bearing inhibitory receptor belonging to the NK receptor family, is crucial for TLR9-mediated type I IFN production by pDCs. Ly49Q is expressed in plasmacytoid DCs (pDCs), macrophages, and neutrophils but not NK cells. Here we showed that Ly49Q regulates both TLR9 and TLR4 signaling by affecting endosome/lysosome behavior. Ly49Q colocalized with CpG in endosome/lysosome compartments. Cells lacking Ly49Q showed a disturbed redistribution of TLR9 and CpG. In particular, CpG-induced tubular endolysosomal extension was impaired in the absence of Ly49Q. Consistent with these findings, cells lacking Ly49Q showed impaired cytokine production in response to CpG-ODN. Our data highlights a novel mechanism by which TLR9 signaling is controlled through the spatiotemporal regulation of membrane trafficking by the ITIM-bearing receptor Ly49Q.
