Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12.
Osteoclasts, cells of myeloid lineage, play a unique role in bone resorption, maintaining skeletal homeostasis in concert with bone-producing osteoblasts. Osteoclast development and maturation (osteoclastogenesis) is driven by receptor activator of NF-kappaB ligand and macrophage-colony stimulating factor and invariably requires a signal initiated by immunoreceptor tyrosine-based activation motif (ITAM)-harboring Fc receptor common gamma chain or DNAX-activating protein (DAP)12 (also referred to as KARAP or TYROBP) that associates with the cognate immunoreceptors. Here, we show that a third adaptor, YINM costimulatory motif-harboring DAP10, triggers osteoclastogenesis and bone remodeling. DAP10-deficient (DAP10(-/-)) mice become osteopetrotic with age, concomitant with a reduction in osteoclasts. The DAP10-associating receptor was identified as myeloid DAP12-associating lectin-1 (MDL-1), whose physiologic function has not been found. MDL-1-mediated stimulation of osteoclast precursor cells resulted in augmented osteoclastogenesis in vitro. MDL-1 associates with both DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages, where DAP10 association depends almost entirely on DAP12, suggesting a formation of MDL-1-DAP12/DAP10 trimolecular complexes harboring ITAM/YINM stimulatory/costimulatory motifs within a complex that could be a novel therapeutic target for skeletal and inflammatory diseases.
Inui
Masanori
M
Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Sendai 980-8575, Japan.
Kikuchi
Yuki
Y
Aoki
Naoko
N
Endo
Shota
S
Maeda
Tsutomu
T
Sugahara-Tobinai
Akiko
A
Fujimura
Shion
S
Nakamura
Akira
A
Kumanogoh
Atsushi
A
Colonna
Marco
M
Takai
Toshiyuki
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000375:Aging / Q000276:immunology / Q000473:pathology; D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D002452:Cell Count; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis; D010022:Osteopetrosis / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C509772:Clec5a protein, mouse; C492355:Hcst protein, mouse; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C484963:Tyrobp protein, mouse