Abstract
Activating killer cell immunoglobulin-like receptors (KIR) in macaques are thought to be derived by genetic recombination of the region encoding the transmembrane and intracellular part of KIR2DL4 and a KIR3D gene. As a result, all macaque activating KIR possess a positively charged arginine residue in the transmembrane region. As human KIR2DL4 associates with the FCER1G (also called Fc receptor-gamma, FcRγ) adaptor, we hypothesized that in contrast to human and great ape the activating KIRs of macaques associate with FcRγ instead of DAP12. By applying co-immunoprecipitation of transfected as well as primary cells, we demonstrate that rhesus macaque KIR3DS05 indeed associates with FcRγ and not with DAP12. This association with FcRγ results in increased and substantially stabilized surface expression of KIR3DS05. In addition, we demonstrate that binding of specific ligands of KIR3DS05, Mamu-A1*001 and A1*011, resulted in signal transduction in the presence of FcRγ in contrast to DAP12.
Highlights
Stimulatory NK cell receptors usually do not transmit signals directly but through association with activation motif-containing accessory proteins DAP12 and FcRg
These findings clearly demonstrate that stimulatory killer cell immunoglobulin-like receptors (KIR) in rhesus macaques interact with the FcRg adaptor protein and not with DAP12
We could unambiguously show by different methods that a prototypical activating KIR protein of rhesus macaques associates with the FcRg and not the DAP12 adaptor protein
Summary
Stimulatory NK cell receptors usually do not transmit signals directly but through association with activation motif-containing accessory proteins DAP12 and FcRg ( called g and encoded by the FCER1G gene). Responsible for this different usage of adaptor proteins are positions of the charged amino acid residues in the transmembrane regions [6]: a lysine and an aspartic acid residue can be found in prototypical KIRs and DAP12 at position 9, respectively, while KIR2DL4 has an arginine and FcRg an aspartic acid residue at position 4 and 3, Macaque Activating KIR and Adaptor respectively Both adaptors contain a single immunoreceptor tyrosine-based activation motif (ITAM) of the sequence D/ ExxYxxL/I(x6–8)YxxL/I in their cytoplasmic region, which is responsible for signal transduction upon binding of a specific ligand by the associated receptor. These adaptor proteins contribute to stabilization of the cell surface expression of interacting stimulatory receptors of different types such as CD16 [7], NKp30 and NKp46 [8], NKp44 [9], KIR [4, 5, 10], CD94/NKG2C [3, 11], ILT1 [12] and many others [13]
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