title: Attenuated natural killer (NK) cell activation through C-type lectin-like receptor NKp80 is due to an anomalous hemi-immunoreceptor tyrosine-based activation motif (HemITAM) with impaired Syk kinase recruitment capacity.
abstract: Cellular cytotoxicity is the hallmark of NK cells mediating both elimination of virus-infected or malignant cells, and modulation of immune responses. NK cytotoxicity is triggered upon ligation of various activating NK cell receptors. Among these is the C-type lectin-like receptor NKp80 which is encoded in the human Natural Killer Gene Complex (NKC) adjacent to its ligand, activation-induced C-type lectin (AICL). NKp80-AICL interaction promotes cytolysis of malignant myeloid cells, but also stimulates the mutual crosstalk between NK cells and monocytes. While many activating NK cell receptors pair with ITAM-bearing adaptors, we recently reported that NKp80 signals via a hemITAM-like sequence in its cytoplasmic domain. Here we molecularly dissect the NKp80 hemITAM and demonstrate that two non-consensus amino acids, in particular arginine 6, critically impair both hemITAM phosphorylation and Syk recruitment. Impaired Syk recruitment results in a substantial attenuation of cytotoxic responses upon NKp80 ligation. Reconstituting the hemITAM consensus or Syk overexpression resulted in robust NKp80-mediated responsiveness. Collectively, our data provide a molecular rationale for the restrained activation potential of NKp80 and illustrate how subtle alterations in signaling motifs determine subsequent cellular responses. They also suggest that non-consensus alterations in the NKp80 hemITAM, as commonly present among mammalian NKp80 sequences, may have evolved to dampen NKp80-mediated cytotoxic responses toward AICL-expressing cells.
authors.affiliation: Institute for Molecular Medicine, Goethe-University Frankfurt am Main, D-60590 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückrich
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinle
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016384:Consensus Sequence; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology*; D037181:Lectins, C-Type / Q000502:physiology*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell / Q000502:physiology*; D015398:Signal Transduction; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431711:KLRF1 protein, human; D037181:Lectins, C-Type; D055607:Receptors, Natural Killer Cell; D018698:Glutamic Acid; D001120:Arginine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases; D005998:Glycine
keywords: Cell Signaling; Cell Surface Receptor; Cellular Immune Response; Immunology; Innate Immunity; NK Receptor; Natural Killer (NK) Cell; Signaling; Syk Kinase