Spatiotemporal regulation of intracellular trafficking of Toll-like receptor 9 by an inhibitory receptor, Ly49Q.
Toll-like receptor (TLR) 9 recognizes unmethylated microorganismal cytosine guanine dinucleotide (CpG) DNA and elicits innate immune responses. However, the regulatory mechanisms of the TLR signaling remain elusive. We recently reported that Ly49Q, an immunoreceptor tyrosine-based inhibitory motif-bearing inhibitory receptor belonging to the natural killer receptor family, is crucial for TLR9-mediated type I interferon production by plasmacytoid dendritic cells. Ly49Q is expressed in plasmacytoid dendritic cells, macrophages, and neutrophils, but not natural killer cells. In this study, we showed that Ly49Q regulates TLR9 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-oligodeoxynucleotide. Our data highlight a novel mechanism by which TLR9 signaling is controlled through the spatiotemporal regulation of membrane trafficking by the immunoreceptor tyrosine-based inhibitory motif-bearing receptor Ly49Q.
Yoshizaki
Mariko
M
Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Tazawa
Aya
A
Kasumi
Eiji
E
Sasawatari
Shigemi
S
Itoh
Kenji
K
Dohi
Taeko
T
Sasazuki
Takehiko
T
Inaba
Kayo
K
Makrigiannis
Andrew P
AP
Toyama-Sorimachi
Noriko
N
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000378:metabolism*
C408982:CPG-oligonucleotide; D016207:Cytokines; C527089:Klra17 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D009838:Oligodeoxyribonucleotides; D034741:RNA, Small Interfering; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9