Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12

Abstract

Osteoclasts, cells of myeloid lineage, play a unique role in bone resorption, maintaining skeletal homeostasis in concert with boneproducing osteoblasts. Osteoclast development and maturation (osteoclastogenesis) is driven by receptor activator of NF-B ligand and macrophage-colony stimulating factor and invariably requires a signal initiated by immunoreceptor tyrosine-based activation motif (ITAM)-harboring Fc receptor common ␥ 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.immunoreceptor tyrosine-based activation motif-harboring adaptor ͉ osteoclast development ͉ synergistic signal

Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice

“…As expected, DAP12-deficient animals were resistant to lethal shock induced by MDL-1 ( Figure 8A). Another adaptor protein, DAP10, has recently been reported to associate with MDL-1 in osteoclasts and to modulate bone remodeling in concert with DAP12 (30). As shown in Figure 8B, DAP10 -/-mice were also protected, indicating that both DAP12 and DAP10 are important for lethal shock triggered by MDL-1.…”

Structural Flexibility of the Macrophage Dengue Virus Receptor CLEC5A

“…DAP12 has no extracellular domain and interacts with CLEC5A through an ionic interaction between polar residues in the transmembrane regions of both proteins (a lysine in CLEC5A and an aspartate in DAP12). The presence of this transmembrane ionic interaction has been shown to be critical for both DAP12 and DAP10 signaling (4,7,34). However, it is unclear how this charge-mediated association within the membrane could transmit information about ligand binding from the extracellular domain of CLEC5A to the intracellular signaling domain of DAP12 as there are no structural studies of the transmembrane interactions of DAP12 or DAP10 with CLEC5A.…”

“…An alternative structure is observed in 1 ⁄ 5 of the simulations where a distinct right-handed CLEC5A-DAP12 heterodimer forms through the same triad of residues but by interacting via an alternative face. In the light of the recent data suggesting a possible CLEC5A-DAP12-DAP10 interaction in osteoclasts, this alternative structure may represent a binding mode that accommodates an additional DAP10 helix (7). Such a structure would represent a right-handed CLEC5A-DAP12-DAP10 heterotrimer, which insulates the polar residues from the hydrophobic core of the membrane.…”

“…Ligand binding by CLEC5A induces the phosphorylation of DAP12 by Src kinases and an interaction with Syk, which triggers further downstream signaling events (6). CLEC5A has been shown to associate with both DAP12 and DAP10 in bone marrow-derived osteoclasts, triggering osteoclastogenesis and bone remodeling (7).…”

Pathogen Strategies to Evade Innate Immune Response: A Signaling Point of View

“…It has been shown that this receptor plays a crucial role in the pathophysiology of dengue virus infection, being directly involved in the production of proinflammatory cytokines by infected macrophages (Chen et www.intechopen.com Watson et al, 2011). CLEC5A has a very short cytoplasmic region lacking a defined signaling motif, yet it transduces intracellular signals trough non-covalent association with the ITAM-bearing adapters DAP10 and DAP12 (Bakker et al, 1999;Inui et al, 2009). DAP10 ITAM motif contains a cytoplasmic sequence that facilitates PI3K recruitment and activation, being possible that it cooperates with DAP12-associated receptors to mediate costimulatory signals (Kerrigan & Brown, 2010).…”