Abstract
Natural killer (NK) cells kill tumor and virus-infected cells using activating NK cell receptors. One of the major NK-activating receptors is NKp46 and its mouse ortholog Ncr1. NKp46/Ncr1 is expressed exclusively on NK cells and on a subset of innate lymphoid cells. NKp46/Ncr1 was shown to be involved in a myriad of pathologies and immunological settings. Specifically, NKp46/Ncr1 was shown to interact with the viral hemagglutinin (HA) protein and with an unknown tumor/cellular ligand. NKp46 and Ncr1 are structurally similar; however, they are substantially different in their glycosylation patterns. Although the human NKp46 carries both O- and N-glycosylations that are essential for its activity, the mouse Ncr1 was predicted to have N-linked glycosylations only. Here we discovered using prediction algorithms and high-performance liquid chromatography analysis that Ncr1 carries two putative novel O-glycosylations, one of which (Thr 225) is conserved in NKp46. We next used surface plasmon resonance, biochemical, mutational and functional in vitro and in vivo assays to demonstrate that the putative O-glycosylations of Ncr1 are critical for its function.
Highlights
Nature killer (NK) cells are lymphocytes of the innate immune system
Because the O-glycosylations of NKp46 were shown to be critical for its recognition of viral HA [1] and as Ncr1 recognizes viral HA [18], we predicted that Ncr1 carries additional, yet unidentified O-glycosylations
To demonstrate that Ncr1 expressed on primary mouse NK cells is O-glycosylated, we initially immunoprecipitated the Ncr1 protein from NK cells obtained from wild-type (WT) (Ncr1+/+) and (Ncr1 knockout Ncr1gfp/gfp) mice [2]
Summary
Nature killer (NK) cells are lymphocytes of the innate immune system. They recognize and eliminate virally infected cells [1,2,3], various malignancies [4,5,6,7], self-cells [8, 9] and bacteria [10,11,12]. The importance of NK cells in general, and NKp46/Ncr in particular was well demonstrated, primarily via the use of Ncr knockout mice, denoted Ncr1gfp/gfp [2, 4, 5, 7, 11, 12, 15,16,17,18].
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