TY  - JOUR
A1  - Rückrich, Thomas
A1  - Steinle, Alexander
T1  - 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
T2  - Journal of biological chemistry
N2  - 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.
Background: The activating NK receptor NKp80 triggers cytotoxicity by human NK cells via a cytoplasmic hemITAM sequence.
Results: A non-consensus hemITAM residue impairs the capacity of NKp80 to recruit Syk kinase and to trigger cytotoxicity.
Conclusion: Unlike typical hemITAM receptors, NKp80 does not efficiently recruit Syk kinase resulting in attenuated effector responses.
Significance: An attenuated cytotoxic responsiveness critically impacts on the immunomodulatory function of NKp80.
KW  - Cell Signaling
KW  - Cell Surface Receptor
KW  - Cellular Immune Response
KW  - Immunology
KW  - Innate Immunity
KW  - Natural Killer (NK) Cell
KW  - Signaling
KW  - NK Receptor
KW  - Syk Kinase
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/76807
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-768071
SN  - 0021-9258
VL  - 288
IS  - 24
SP  - 17725
EP  - 17733
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -